Background: Understanding the determinants of major depression in sub-Saharan Africa is important for planning effective intervention strategies. Objective: To investigate the social and life-event determinants of major depressive disorder in the African socio-cultural context of rural Uganda. Methods: A cross-section survey was carried out in 14 districts in Uganda from 1st June 2003-30th October 2004. 4660 randomly selected respondents (15 years and above) were interviewed. The primary outcome was the presence of major depressive disorder as assessed by the Hopkins Symptom Checklist (HSCL-25). Results: The prevalence of major depressive disorder was 29.3% (95% confidence interval, 28.0%-30.6%). Factors independently associated with depression in both genders included: the ecological factor, district; age (increase with each age category after 35 years); indices of poverty and deprivation (no formal education, having no employment, broken family, and socio-economic classes III-V). Only a few adverse life events, notably those suggestive of a disrupted family background (death of a father in females and death of a mother in males) were associated with increased risk. Conclusion: Socioeconomic factors operating at both ecological and the individual level are the strongest independent determinants of depression. Adverse life events were less strongly associated with depression in this sample.