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WHO guidelines recommend cotrimoxazole prophylaxis (CTXP) in all HIV-exposed negative infants who are still breastfeeding. This is based on the evidence of efficacy in HIV-infected infants, but there is no evidence of benefit in HIV-negative, breast-fed infants. We assessed the impact of CTXP on diarrhoeal and respiratory morbidity in breast-fed, HIV-exposed negative infants in a community programme. CTXP for more than 60 days showed no consistent evidence of benefit for incidence of lower respiratory tract infection [incidence rate ratio (IRR) 0.71, 95% confidence interval (CI) 0.39–1.26; P = 0.241] but an increased incidence of diarrhoea (IRR = 1.38, 95% CI 0.98–1.94; P = 0.065). The guidelines should be reconsidered by conducting a randomized control trial.