BACKGROUND: We report the design and analysis of a streamlined approach to the delivery of antiretroviral therapy (ART) that minimized risk for emergence of ART drug resistance (ART-DR) in a resource-limited setting. METHODS: The algorithm of care for persons with HIV comprised generic, fixed-dose, twice-daily stavudine, lamivudine and nevirapine (GPO-VIR), scheduled and unannounced pill counts and measurement of viral load at months 6 and 18 after initiation of ART. We evaluated adherence as measured by pill counts, HIV suppression and programmatic costs. RESULTS: Over a 4-year period, 214 of 330 patients (64.8%) were enrolled; baseline median CD4 count was 84 cells/microL. At month 1, nine patients (4.2%) discontinued GPO-VIR because of skin rash. At month 6, 199 patients (93%) achieved viral load < or =400 HIV-1 RNA copies/mL, with current alcohol use the sole predictor of treatment failure [adjusted Relative Risk (aRR)=1.67; 95% confidence interval=1.05-2.48; P<0.001]. Most patients (97%) with HIV suppression at month 6 had viral loads < or =50 copies/mL at month 18; all had > or =75% visit compliance and 192 (98%) had > or =75% adherence measured by pill counts. The estimated annual costs were $111.92 per patient for the pill counts, home visits and viral load measurement. CONCLUSIONS: Secure ART delivery, while minimizing risk for non-adherence and ART-DR, is clinically and economically feasible in this resource-limited setting.