The SPANC study is a prospective cohort study of the national history of anal human papillomavirus (HPV) infection and anal cellular abnormalities in homosexual men aged 35 years and above in Sydney. It is expected that the study results will be influential in the possible development of an anal cancer screening program in high-risk populations. Data on the natural history of anal HPV infection in homosexual men recruited from community-based settings are rare. We aim to recruit a total of 600 men, 360 HIV-negative and 240 HIV-positive. This will make the SPANC study one of the biggest ongoing anal HPV natural history study in the world to provide critical data on the incidence and clearance of anal HPV infection, progression and regression of pre-cancerous HPV associated anal lesions, the potential psychological impact on men who participate anal cancer screening programs, and the cost-effectiveness of rolling out these programs.