Objectives: To evaluate severe (grade 3/4) morbidity and mortality in HIV-exposed, uninfected infants. Design: Secondary data analysis of The Breastfeeding, Antiretrovirals, and Nutrition (BAN) clinical trial. Methods: BAN randomized 2369 mother-infant pairs to maternal, infant, or no extended antiretroviral prophylaxis during breastfeeding. Morbidity outcomes examined were pneumonia/serious febrile illness, diarrhea/growth faltering, and malaria. Infant death was defined as neonatal (<30 days of life), and postneonatal (31 days to 48 weeks of life). Cox proportional hazards models were used to evaluate the effect of covariates on infant morbidity and mortality. Results: The rate of pneumonia/serious febrile illness was highest in the first 12 weeks (0.83/100 person-weeks) before rapidly decreasing; rates of all morbidity outcomes increased after 24 weeks. Rates of pneumonia/serious febrile illness and diarrhea/growth faltering were higher during the rainy season. Prophylactic infant cotrimoxazole significantly decreased the rates of all morbidity outcomes. White blood cell (WBC) count less than 9000/ml at birth was associated with increased diarrhea/growth faltering [adjusted hazard ratio (aHR) 1.73, P = 0.04] and malaria (aHR 2.18, P = 0.02). Low birth weight (2000-2499 g) was associated with neonatal death (aHR 12.3, P< 0.001). Factors associated with postneonatal death included rainy season (aHR 4.24, P = 0.002), infant cotrimoxazole (aHR 0.48, P = 0.03), and low infant WBC count at birth (aHR 2.53, P = 0.02). Conclusion: Infant morbidity rates increased after 24 weeks, when BAN infants weaned. Introduction of prophylactic cotrimoxazole was associated with reduced rates of morbidity and mortality in HIV-exposed uninfected infants. Unexpectedly, a low WBCcount at birth was significantly associated with later infant morbidity and mortality in this cohort. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins AIDS 2013, 27:749-759