Zidovudine (AZT) treatment during pregnancy, delivery, and the postnatal period is associated with adverse effects in the neonate such as bone marrow suppression, elevation in aspartate aminotransferase activity, and lactic acidosis. With antiretroviral therapy (ART) now being recommended for life in HIV-infected pregnant women, infants born to these mothers and on breastfeeds are going to be exposed to antiretrovirals for a longer duration. We report a rare case of an HIV-exposed infant who received AZT prophylaxis for 6 weeks after birth and was on exclusive breastfeed while the mother was on ART and presented with unexplained severe metabolic acidosis and encephalopathy.