BACKGROUND: A complete blood count (CBC) with white blood cell differential is commonly ordered to evaluate newborns at risk for sepsis. OBJECTIVES: To quantify how well components of the CBC predict sepsis in the first 72 hours after birth. METHODS: For this retrospective cross-sectional study we identified 67 623 term and late-preterm (>/= 34 weeks gestation) newborns from 12 northern California Kaiser hospitals and 1 Boston, Massachusetts hospital who had a CBC and blood culture within 1 hour of each other at <72 hours of age. We compared CBC results among newborns whose blood cultures were and were not positive and quantified discrimination by using receiver operating characteristic curves and likelihood ratios. RESULTS: Blood cultures of 245 infants (3.6 of 1000 tested newborns) were positive. Mean white blood cell (WBC) counts and mean absolute neutrophil counts (ANCs) were lower, and mean proportions of immature neutrophils were higher in newborns with infection; platelet counts did not differ. Discrimination improved with age in the first few hours, especially for WBC counts and ANCs (eg, the area under the receiver operating characteristic curve for WBC counts was 0.52 at <1 hour and 0.87 at >/= 4 hours). Both WBC counts and ANCs were most informative when very low (eg, the likelihood ratio for ANC < 1000 was 115 at >/= 4 hours). No test was very sensitive; the lowest likelihood ratio (for WBC count >/= 20 000 at >/= 4 hours) was 0.16. CONCLUSION: Optimal interpretation of the CBC requires using interval likelihood ratios for the newborn’s age in hours.