Background Few randomized trials comparing antiretroviral therapy (ART) regimens have been conducted in resource-limited settings. Methods In the Republic of South Africa, antiretroviral-naive HIV-infected individuals >14 years old, with <200 CD4+ cells/mm3 or prior AIDS diagnosis were randomized to: EFV or LPV/r with either ZDV+ddI or d4T+3TC in an open-label 2×2 factorial study and followed for: the primary outcome of AIDS or death; pre-specified secondary outcomes including CD4+ and viral load changes, treatment discontinuations and grade 4 events. Results 1771 persons were randomized and followed for a median of 24.7 months. AIDS or death occurred among 163 participants assigned EFV and 157 LPV/r (HR=1.04; 95% CI 0.84–1.30) and among 170 assigned ZDV+ddI and 150 assigned d4T+3TC (HR=1.15; 95% CI: 0.93–1.44). HIV RNA was lower (p<0.001) and CD4+ count greater (p<.01) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI; however, more participants discontinued d4T due to toxicity (12.6%) than other treatments (<5%). Conclusion EFV or LPV/r are effective components of first-line ART. The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest these treatments be used cautiously as initial therapy. Trial Registration clinicaltrials.gov Identifier: NCT00342355