The Tshepo study was the first clinical trial to evaluate outcomes of adults receiving nevirapine (NVP)-based versus efavirenz (EFV)-based combination antiretroviral therapy (cART) in Botswana. This was a 3 year study (n=650) comparing the efficacy and tolerability of various first-line cART regimens, stratified by baseline CD4(+): <200 (low) vs. 201-350 (high). Using targeted maximum likelihood estimation (TMLE), we retrospectively evaluated the causal effect of assigned NNRTI on time to virologic failure or death [intent-to-treat (ITT)] and time to minimum of virologic failure, death, or treatment modifying toxicity [time to loss of virological response (TLOVR)] by sex and baseline CD4(+). Sex did significantly modify the effect of EFV versus NVP for both the ITT and TLOVR outcomes with risk differences in the probability of survival of males versus the females of approximately 6% (p=0.015) and 12% (p=0.001), respectively. Baseline CD4(+) also modified the effect of EFV versus NVP for the TLOVR outcome, with a mean difference in survival probability of approximately 12% (p=0.023) in the high versus low CD4(+) cell count group. TMLE appears to be an efficient technique that allows for the clinically meaningful delineation and interpretation of the causal effect of NNRTI treatment and effect modification by sex and baseline CD4(+) cell count strata in this study. EFV-treated women and NVP-treated men had more favorable cART outcomes. In addition, adults initiating EFV-based cART at higher baseline CD4(+) cell count values had more favorable outcomes compared to those initiating NVP-based cART.