MSc (Med), Epidemiology and Biostatistics, Faculty of Health Sciences, University of the Witwatersrand / Background: Few studies have compared the sociodemographic characteristics and treatment outcomes of HIV/AIDS patients in rural and urban South Africa. Aim: This study compared the baseline socio-demographic characteristics and treatment outcomes (time to mortality, immunologic and virologic response) of HAART-naïve patients in urban and rural South Africa. Methodology: A secondary analysis of data obtained from the Themba Lethu Clinic, Helen Joseph Hospital, Johannesburg (urban site) and the ACTS clinic, Mpumalanga (rural site) from January 2005 to December 2008 was used to make comparison of baseline socio-demographic and clinical characteristics of patients in both cohorts. The survival experience and predictors of mortality was performed using Kaplan – Meier survival analysis and Cox proportional hazards models while effects on immunologic and virologic responses to HAART were modeled using logistic regression. Results: At initiation of HAART, the rural cohort had similar CD4 count and body mass index, but lower haemoglobin levels, compared to the urban cohort. The median follow up time for both cohorts was 566 days with the urban cohort having a mortality rate of 5.6/100 person-years compared to the 4.8/100 person-years of the rural cohort. CD4 count, BMI and WHO stage were predictors of mortality in both cohorts. Logistic regression models for virologic and immunologic response did not show any difference by site in the multivariate models. Conclusion: Though there are differences in the baseline sociodemographic and clinical characteristics of rural and urban patients starting HAART for the first time, achievement of immunologic and virologic response at 6 months of therapy were similar in both cohorts. Continued public health enlightenment campaigns and nutritional support programs should be undertaken to ensure patients present early and benefit from treatment.