BACKGROUND: In resource-limited settings, people with disabilities have been left behind in the response to HIV. In the HandiVIH study, we estimate and compare HIV prevalence and associated risk factors between people with and without disabilities. METHODS: In this cross-sectional, population-based, observational study, we used two-phase random sampling to recruit adults with disabilities and a control group matched for age, sex, and residential location from households of the general population. We used the Washington Group Short Set of Questions on Disability to identify people with disabilities. We administered an HIV test and a life-course history interview to participants. The primary outcome was the prevalence of HIV among participants with and without disabilities. FINDINGS: Between Oct 2, 2014, and Nov 30, 2015, we recruited 807 people with disabilities and 807 participants without disabilities from Yaounde, Cameroon. 28 of 716 people in the control population had a positive HIV test result (crude prevalence 3.9%, 95% CI 2.9-5.3) compared with 50 of 739 people with disabilities (6.8%, 5.0-8.6; conditional odds ratio [OR] 1.7; p=0.04). Women with disabilities were more often involved in paid sexual relationships than were women without disabilities (2.5% vs 0.5%, p=0.05). People with disabilities were also at increased risk of sexual violence than were women without disabilities (11.0% vs 7.5%, OR 1.5; p=0.01). Sexual violence and sex work were strongly associated with increased risk of HIV infection among participants with disabilities but not among controls (OR 3.0, 95% CI 1.6-5.6 for sexual violence and 12.3, 4.4-34.6 for sex work). Analyses were done in men and women. INTERPRETATION: The higher prevalence of HIV infection in people with disabilities than people without disabilities reflects a higher exposure to HIV infection as well as the presence of disability-associated HIV infection. The susceptibility of people with disabilities to HIV infection seems to be shaped by social and environmental factors. Research is needed to inform firm recommendations on how to protect this vulnerable population.