In June 2000, de Mistura was Special Rapporteur during the Fribourg Forum on Regional Cooperation and Coordination in Crisis Management for Europe and the Newly Independent States.
Until 2001, he was Director of the United Nations Information Centre in Rome.

From 2001 to 2004, Staffan de Mistura served as Personal Representative of the Secretary-General Kofi Annan in Southern Lebanon.
One of his major achievements in that post was to set up and organise a successful de-mining operation.
He then went on to serve as Deputy Special Representative for Iraq for 15 months, starting in January 2005.
During his tenure, he was keen to portray an optimistic view of Iraq and its chances of recovery, highlighting the hard work the UN were putting in behind the scenes to provide Iraqis with a better standard of living.

After that, he became Director of the UN Staff College in Turin, Italy, a post he retained until 11 September 2007, when Ban Ki-moon appointed him as his Special Representative (SRSG) for Iraq.
He was the successor of SRSG Ashraf Qazi and assumed his responsibilities in the Mission Area on 5 November and in Baghdad on 11 November 2007.
In the weeks leading up to the appointment, it was reported that politicians in Baghdad strongly favoured a former Romanian envoy to Iraq, Radu Onofrei.
However, it was later revealed through Wikileaks that it was the Romanian government that lobbied the US to favor Mr. Onofrei.

In July 2009, Staffan de Mistura left Iraq to become the Deputy Executive Director for External Relations of the World Food Programme in Rome.

In January 2010, Richard Holbrooke, the U.S. special representative for Afghanistan and Pakistan, revealed that de Mistura had been offered the job as the U.N. special representative in Afghanistan, replacing Kai Eide.
The New York Times noted in an editorial that UN Secretary General Ban Ki-moon had also been considering Jean-Marie Guéhenno of France and Ian Martin of Britain for the Kabul mission.
By the end of January 2010, Ban announced his intention to appoint de Mistura in March 2010 as Special Representative of the Secretary General (SRSG) in Afghanistan and Chief of the United Nations Assistance Mission in Afghanistan (UNAMA).

While U.S. President Barack Obama laid the blame for the massacre of U.N. officials in Mazar-i-Sharif on the Afghans, Staffan de Mistura said "I don't think we should be blaming any Afghan.
We should be blaming the person who produced the news—the one who burned the Koran."

On 28 November 2011, he was nominated Undersecretary of Foreign Affairs in Italy's technocratic cabinet headed by Mario Monti.

In May 2013, the Italian Government appointed Deputy Foreign Minister Staffan de Mistura as the Special Envoy of the Prime Minister of Italy to resolve the case of two Italian Navy marines, held in India since February 2012, who were accused by the Indian authorities for allegedly killing by mistake two Indian fishermen, believing that they were pirates, when deployed on an Italian-flagged merchant vessel Enrica Lexie.
The 2012 Italian Navy Marines shooting incident in the Laccadive Sea strained diplomatic relations between Italy and India.
Staffan de Mistura has been mandated to find a "fair, positive and acceptable solution" with Indian judicial authorities to ensure a quick trial and return of Massimiliano Latorre and Salvatore Girone to Italy.
In June 2000, de Mistura was Special Rapporteur during the Fribourg Forum on Regional Cooperation and Coordination in Crisis Management for Europe and the Newly Independent States. Until 2001, he was Director of the United Nations Information Centre in Rome.
From 2001 to 2004, Staffan de Mistura served as Personal Representative of the Secretary-General Kofi Annan in Southern Lebanon. One of his major achievements in that post was to set up and organise a successful de-mining operation. He then went on to serve as Deputy Special Representative for Iraq for 15 months, starting in January 2005. During his tenure, he was keen to portray an optimistic view of Iraq and its chances of recovery, highlighting the hard work the UN were putting in behind the scenes to provide Iraqis with a better standard of living.
After that, he became Director of the UN Staff College in Turin, Italy, a post he retained until 11 September 2007, when Ban Ki-moon appointed him as his Special Representative (SRSG) for Iraq. He was the successor of SRSG Ashraf Qazi and assumed his responsibilities in the Mission Area on 5 November and in Baghdad on 11 November 2007. In the weeks leading up to the appointment, it was reported that politicians in Baghdad strongly favoured a former Romanian envoy to Iraq, Radu Onofrei. However, it was later revealed through Wikileaks that it was the Romanian government that lobbied the US to favor Mr. Onofrei.
In July 2009, Staffan de Mistura left Iraq to become the Deputy Executive Director for External Relations of the World Food Programme in Rome.
In January 2010, Richard Holbrooke, the U.S. special representative for Afghanistan and Pakistan, revealed that de Mistura had been offered the job as the U.N. special representative in Afghanistan, replacing Kai Eide. The New York Times noted in an editorial that UN Secretary General Ban Ki-moon had also been considering Jean-Marie Guéhenno of France and Ian Martin of Britain for the Kabul mission. By the end of January 2010, Ban announced his intention to appoint de Mistura in March 2010 as Special Representative of the Secretary General (SRSG) in Afghanistan and Chief of the United Nations Assistance Mission in Afghanistan (UNAMA).
While U.S. President Barack Obama laid the blame for the massacre of U.N. officials in Mazar-i-Sharif on the Afghans, Staffan de Mistura said "I don't think we should be blaming any Afghan. We should be blaming the person who produced the news—the one who burned the Koran."
On 28 November 2011, he was nominated Undersecretary of Foreign Affairs in Italy's technocratic cabinet headed by Mario Monti.
In May 2013, the Italian Government appointed Deputy Foreign Minister Staffan de Mistura as the Special Envoy of the Prime Minister of Italy to resolve the case of two Italian Navy marines, held in India since February 2012, who were accused by the Indian authorities for allegedly killing by mistake two Indian fishermen, believing that they were pirates, when deployed on an Italian-flagged merchant vessel Enrica Lexie. The 2012 Italian Navy Marines shooting incident in the Laccadive Sea strained diplomatic relations between Italy and India. Staffan de Mistura has been mandated to find a "fair, positive and acceptable solution" with Indian judicial authorities to ensure a quick trial and return of Massimiliano Latorre and Salvatore Girone to Italy.
Staffan de Mistura