OBJECTIVE: To determine the effectiveness of efavirenz versus nevirapine in initial antiretroviral therapy regimens for adults in sub-Saharan Africa. DESIGN: Observational cohort study. METHODS: Study participants were 2817 HIV-infected, highly active antiretroviral therapy-naive adults who began nevirapine-based or efavirenz-based highly active antiretroviral therapy between January 1998 and September 2004 via a private-sector HIV/AIDS program in nine countries of southern Africa. The primary outcome was time to virologic failure (two measurements of viral loads >or=400 copies/ml). Secondary outcomes included all-cause mortality, time to viral load less than 400 copies/ml, pharmacy-claim adherence, and discontinuation of nevirapine or efavirenz without virologic failure. RESULTS: The median follow-up period was 2.0 years (interquartile range 1.2-2.6). Patients started on nevirapine were significantly less likely than those started on efavirenz to achieve high adherence, whether defined as 100% (30.2 versus 38.1%, P < 0.002) or more than 90% (44.8 versus 49.4%, P < 0.02) pharmacy-claim adherence. In a multivariate analysis, patients on nevirapine had greater risk of virologic failure [hazard ratio (HR 1.52; 95% confidence interval (CI) 1.24-1.86)], death (2.17; 1.31-3.60), and regimen discontinuation (1.67; 1.32-2.11). Switching from nevirapine to efavirenz had no significant virologic effect, whereas switching from efavirenz to nevirapine resulted in significantly slower time to suppression (hazard ratio 0.58, 95% confidence interval 0.35-0.93) and faster time to failure (hazard ratio 3.92; 95% confidence interval 1.61-9.55) than remaining on efavirenz. CONCLUSION: In initial highly active antiretroviral therapy regimens, efavirenz was associated with superior virologic and clinical outcomes than nevirapine, suggesting that efavirenz might be the preferred nonnucleoside reverse transcriptase inhibitor in resource-limited settings. However, its higher cost and potential teratogenicity are important barriers to implementation.