Background: Despite the benefits of exclusive breastfeeding (EBF), exposure to HIV from breast milk has relegated EBF to an option only when formula feeding is not affordable, feasible, safe, and sustainable. Mixed feeding remains the norm in sub-Saharan Africa. Objective: We evaluated whether the duration of EBF was associated with mortality and HIV infection in children followed to <= 5 y of age. Methods: A total of 690 mother-infant pairs from the Trial of Vitamins with information on infant feeding, HIV status, and at least one visit in the first year were included in the analysis. The duration of EBF was defined in months as a time-varying covariate at each follow-up visit. Associations of the duration of EBF with mortality, HIV infection, and HIV infection or death were estimated by using Cox proportional hazards models and Kaplan-Meier survival curves. Results: A 1-mo increase in EBF was associated with a 49% reduction in early infant mortality in the first 6 mo of life (RR: 0.51; 95% CI: 0.28, 0.93) and a nonsignificant 15% reduction in risk of HIV infection or death (RR: 0.85; 95% CI: 0.71, 1.01; P = 0.07) over the first 5 y of life. EBF was not associated with HIV infection (RR: 0.93; 95% CI: 0.76, 1.15). Conclusion: Longer EBF by HIV-positive mothers was associated with reduced mortality in the first 6 mo of life without increased HIV infection, which makes EBF the best option for women who cannot sustain exclusive formula feeding. This trial was registered at clinicaltrials.gov as NCT00197743. Am J Clin Nutr 2012;96:1071-8.Version of Record