Objective: To assess serious gastroenteritis risk and mortality associated with early cessation of breastfeeding in infants enrolled in 2 prevention of maternal-to-child HIV-transmission trials in Uganda.Methods: We used hazard rates to evaluate serious gastroenteritis events by month of age and mortality among HIV-exposed uninfected infants enrolled in the HIV Network for Prevention Trials (HIVNET 012) (1997–2001) and HIV hyperimmune globulin (HIVIGLOB)/nevirapine (NVP) (2004–2007) trials. HIV-infected mothers were counseled using local infant feeding guidelines current at the time.Results: Breastfeeding cessation occurred earlier in HIVIGLOB/NVP compared with HIVNET 012 (median 4.0 versus 9.3 months,P,0.001). Rates of serious gastroenteritis were higher in HIVIGLOB/NVP (8.0/1000 child-months) than in HIVNET 012 (3.1/1000 child-months; P , 0.001). Serious gastroenteritis events also peaked earlier at 3–4 and 7–8 months (16.2/1000 and 15.0/1000 child-months,respectively) compared with HIVNET 012 at 9–10 months (20.8/1000 child-months). All cause infant mortality did not statistically differ between the HIVIGLOB/NVP and the HIVNET 012 trials [3.2/1000 versus 2.0/1000 child-months, respectively (P = 0.10)].Conclusions: Early breastfeeding cessation seen in the HIVIGLOB/NVP trial was associated with increased risk of serious gastroenteritis among HIV-exposed uninfected infants when compared with later breastfeeding cessation in the HIVNET 012 trial.Testing interventions, which could decrease HIV transmission through breastfeeding and allow safe