Current WHO guidelines for developing countries recommend efavirenz (EFV) and nevirapine (NVP) for first-line antiretroviral treatment (ART). This paper compares the effectiveness of EFV and NVP among ART-naive patients initiating treatment at 56 public health facilities in South Africa between January 2004 and December 2007. Participants were assigned to the EFV or NVP cohorts depending on their baseline ART regimen. Mortality, viral load suppression after 6 months and ART regimen change were compared between the cohorts using Cox proportional hazards models and logistic regression. At initiation, 19 441 (71.1) patients started EFV and 7909 (28.9) started NVP treatment. The median follow-up period was 9.5 months (IQR 4.617.7). After adjustment, mortality was similar in the two cohorts, (adjusted HR 1.07, 95 CI 0.891.28). Viral load suppression at 6 months was higher in the EFV cohort overall (adjusted odds ratio [AOR] 1.29, 95 CI 1.051.59) and in women aged 1640 years (AOR 1.35, 95 CI 1.111.63) and women with CD4 counts 25 cells/L (AOR 1.95, 95 CI 1.013.76). Patients starting on EFV were 47 less likely to change regimen (AOR 0.53, 95 CI 0.480.59). These findings suggest the superior effectiveness of EFV for first-line ART compared with NVP and should be considered during development of future ART guidelines for high-burden regions.