Major depressive disorder (MDD) is projected to become the second most common cause of disability by 2020 calling for a better understanding its antecedents across the lifespan and in diverse socio-cultural settings. In this paper we describe the risk factors of MDD among older people (50 years +) living in HIV-endemic central and southwestern Uganda. A cross-sectional study was undertaken among 471 respondents (50 years +) participating in the Wellbeing of Older People's Study cohort of the MRC/UVRI Uganda research Unit on AIDS in Uganda. Participants were from five strata: HIV negative, HIV positive on ART, HIV positive not on ART, having an adult child on ART, and having an adult child who died of HIV. Overall MDD prevalence was 9.2% (95% CI 6.7-12.2%) with a prevalence among males of 7.4% (95% CI 4.0-12.3%) and females of 10.3% (95% CI 7.0-14.3%). Factors significantly associated with MDD included: declining socio-economic status, increasing disability scores, decreasing mean grip strength, reported back pain, and not having hypertension. Marginally associated with MDD was being HIV infected and not on ART.