At the apex of his political life, Ōhira came to represent what were known as "mainstream factions" within the Liberal Democratic Party (LDP) which put him at odds with Prime Minister Takeo Fukuda, who led what were known as an "anti-mainstream" faction.
Ōhira served as foreign minister in the cabinet of Kakuei Tanaka until mid-July 1974.
In a cabinet reshuffle in July 1974, he was replaced by Toshio Kimura as foreign minister and then appointed the finance minister, replacing Takeo Fukuda.

Ōhira was elected to the presidency of the LDP in late 1978.
On 7 December 1978, he was appointed 68th Prime Minister, successfully pushing Takeo Fukuda from his position.

Ōhira was the sixth Christian to hold this office after Hara Takashi, Takahashi Korekiyo, Ichirō Hatoyama, Tetsu Katayama, and Shigeru Yoshida.

In the general election of 1979, the LDP narrowly failed to win an outright majority, but enough independent members of the Diet joined the party to enable Ōhira to remain in office, and he was duly reappointed on 9 November of that year.
On 16 May 1980, a vote of no confidence was held in the Diet.

Ōhira expected the motion to fail, and was visibly shaken when it passed 243–187.
69 members of his own LDP, including Fukuda, abstained.
Given the choice of resigning or calling new elections, Ōhira chose the latter and began campaigning for LDP candidates.
He was hospitalized for exhaustion on 31 May and died of a massive heart attack 12 days later.

Chief Cabinet Secretary Masayoshi Ito acted in Ōhira's place as deputy after his death.
Yoshio Sakurauchi, the Secretary General of LDP, led the LDP to its greatest victory in fifteen years, capitalizing on the "sympathy vote" generated by Ōhira's death.
The Prime Minister was succeeded by Zenkō Suzuki after the election.
At the apex of his political life, Ōhira came to represent what were known as "mainstream factions" within the Liberal Democratic Party (LDP) which put him at odds with Prime Minister Takeo Fukuda, who led what were known as an "anti-mainstream" faction. Ōhira served as foreign minister in the cabinet of Kakuei Tanaka until mid-July 1974. In a cabinet reshuffle in July 1974, he was replaced by Toshio Kimura as foreign minister and then appointed the finance minister, replacing Takeo Fukuda. 
Ōhira was elected to the presidency of the LDP in late 1978. On 7 December 1978, he was appointed 68th Prime Minister, successfully pushing Takeo Fukuda from his position.
Ōhira was the sixth Christian to hold this office after Hara Takashi, Takahashi Korekiyo, Ichirō Hatoyama, Tetsu Katayama, and Shigeru Yoshida.
In the general election of 1979, the LDP narrowly failed to win an outright majority, but enough independent members of the Diet joined the party to enable Ōhira to remain in office, and he was duly reappointed on 9 November of that year. On 16 May 1980, a vote of no confidence was held in the Diet.
Ōhira expected the motion to fail, and was visibly shaken when it passed 243–187. 69 members of his own LDP, including Fukuda, abstained. Given the choice of resigning or calling new elections, Ōhira chose the latter and began campaigning for LDP candidates. He was hospitalized for exhaustion on 31 May and died of a massive heart attack 12 days later.
Chief Cabinet Secretary Masayoshi Ito acted in Ōhira's place as deputy after his death. Yoshio Sakurauchi, the Secretary General of LDP, led the LDP to its greatest victory in fifteen years, capitalizing on the "sympathy vote" generated by Ōhira's death. The Prime Minister was succeeded by Zenkō Suzuki after the election.
Masayoshi Ōhira