Background. After the scale-up of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) infection in Africa, increasing numbers of patients have pretreatment drug resistance. Methods. In a large multicountry cohort of patients starting standard first-line ART in six African countries, pol genotyping was retrospectively performed if viral load (VL) >1000 cps/mL. Pretreatment drug resistance was defined as a decreased susceptibility to >1 prescribed drug. We assessed the effect of pretreatment drug resistance on all-cause mortality, new AIDS events and switch to second-line ART due to presumed treatment failure, using Cox models. Results. Among 2579 participants for whom a pretreatment genotype was available, 5.5% had pretreatment drug resistance. Pretreatment drug resistance was associated with an increased risk of regimen switch (adjusted hazard ratio [aHR] 3.80; 95% confidence interval [CI], 1.49-9.68; P =. 005) but was not associated with mortality (aHR 0.75, 95% CI,. 24-2.35; P =. 617) or new AIDS events (aHR 1.06, 95% CI,. 68-1.64; P =. 807). During three years of follow up, 106 (4.1%) participants switched to second-line, of whom 18 (17.0%) switched with VL < 1000 cps/mL, 7 (6.6%) with VL > 1000 cps/mL and no drug resistance mutations (DRMs), 46 (43.4%) with VL > 1000 cps/mL and >1 DRMs; no HIV RNA data was available for 32 (30.2%) participants. Conclusions. Given rising pretreatment HIV drug resistance levels in sub-Saharan Africa, these findings underscore the need for expanded access to second-line ART. VL monitoring can improve the accuracy of failure detection and efficiency of switching practices.