To identify the predictors of repeat exchange transfusion among infants with severe hyperbilirubinemia. Retrospective cross-sectional study. A referral children's hospital in inner-city Lagos, Nigeria. Infants who received exchange transfusion for severe hyperbilirubinemia from January 2012 to December 2014. None. The predictors of repeat exchange transfusion were identified among all infants who had at least one exchange transfusion using multivariable logistic regression. A total of 352 infants with mean peak total serum bilirubin of 26.32 ± 7.96 mg/dL received exchange transfusion; of these, 49 (13.9%) with mean peak total serum bilirubin of 32.85 ± 10.54 mg/dL had repeat exchange transfusion. More than two thirds of infants who received exchange transfusion and repeat exchange transfusion were male, and at least one third had ABO incompatibility. No infant had more than two exchange transfusions. The mean age of admission was approximately 5 days (range, 1-14 d). Peak total serum bilirubin greater than or equal to 30 mg/dL (odds ratio, 2.88; 95% CI, 1.46-5.70) and acute bilirubin encephalopathy (odds ratio, 2.37; 95% CI, 1.18-4.77) were predictive of repeat exchange transfusion. Acute bilirubin encephalopathy and excessive total serum bilirubin levels at least 30 mg/dL are predictive of repeat exchange transfusion. A risk assessment framework that combines total serum bilirubin levels, acute bilirubin encephalopathy status, and risk factors of neurotoxicity should be considered for the timely detection and monitoring of infants at risk of repeat exchange transfusion.