OBJECTIVES: (1) To validate a previously reported risk index for predicting total serum bilirubin (TSB) levels of 25 mg/dL (428 micromol/L) or higher; (2) to combine a subset of this index with TSB levels measured at less than 48 hours to predict subsequent TSB levels of 20 mg/dL (342 micromol/L) or higher. DESIGN: Nested case-control study using electronic and paper records (study 1). Retrospective cohort study using electronic records only (study 2). SETTING: Northern California Kaiser Permanente hospitals. PATIENTS: Subjects for both studies were newborns weighing 2000 g or more and of 36 weeks’ or more gestation. The validation study included 67 cases born 1997-1998 who developed TSB levels of 25 mg/dL or higher at less than 30 days and 208 randomly selected control subjects. Subjects for study 2 were 5706 newborns who both were discharged from the hospital and had a TSB level measured at less than 48 hours. RESULTS: The risk index performed similarly in the validation group, born in 1997-1998, and the derivation group, born in 1995-1996 (area under the receiver operating characteristic curve = 0.83 vs 0.84). Of the 5706 newborns with TSB levels measured before 48 hours, 270 (4.7%) developed a TSB level of 20 mg/dL or higher. Of these, 254 (94%) had a TSB level at the 75th percentile or higher at less than 48 hours. The risk index improved prediction over the TSB level alone, largely owing to the effect of gestational age. For example, for those with a TSB level at the 95th percentile or higher at less than 48 hours, the risk increased from 9% for newborns born at 40 weeks’ or more gestation to 42% for those born at 36 weeks. CONCLUSION: Clinical risk factors significantly improve prediction of subsequent hyperbilirubinemia compared with early TSB levels alone, especially in those with early TSB levels above the 75th percentile.