OBJECTIVE: To examine the clinical significance of elevated conjugated bilirubin (CB) levels in newborns. STUDY DESIGN: This retrospective study evaluated a birth cohort of 271 186 full-term newborns born within a Northern California hospital network from 1995 to 2004. All CB and direct bilirubin (DB) levels were available in a database and were correlated with the patients’ inpatient and outpatient International Classification of Diseases, 9th Revision diagnoses. RESULTS: The 99th percentile for CB is 0.5 mg/dL, and the 99th percentile for DB is 2.1 mg/dL. CB levels between 0.5 and 1.9 mg/dL can be associated with infection, but most often remain unexplained. Liver and biliary disease become increasingly likely as CB levels increase; for CB >/=5 mg/dL, 47% of newborns have biliary disease and 43% have liver disease. CONCLUSIONS: CB and DB levels are not interchangeable. In newborns with CB levels >/=0.5 mg/dL and <2 mg/dL, infection must be ruled out, and the newborn should be observed. In newborns with levels >/=2 mg/dL, a more in-depth assessment of the hepatobiliary system is indicated.