Neonatal infection is the main complication of prelabor rupture of membranes (PROM). We studied the accuracy of measuring C-reactive protein (CRP) and leukocytes in maternal serum to predict neonatal infection. We performed a retrospective cohort study in two hospitals in the Netherlands between 2003 and 2006. We included consecutive women hospitalized for PROM. In both hospitals, CRP and leukocytes were measured routinely in maternal serum every 2 days until delivery. End points considered were clinical neonatal infection and proven neonatal sepsis. The accuracy of CRP and leukocytes was assessed using receiver operating characteristic (ROC) analysis. We included 299 women with PROM, 12 of whom had a twin pregnancy. Gestational age at inclusion varied between 26 weeks and 0 days and 41 weeks and 5 days with a median of 37 weeks and 3 days. In 47 women (16%), the neonate developed a clinical infection. The areas under the ROC curve of CRP and leukocytes in the prediction of clinical neonatal infection were 0.61 and 0.62, respectively. Of the 47 infected neonates, six neonates (2%) had a proven neonatal sepsis. In the mothers of these septic neonates, maternal CRP did not rise above 50 mg/L and leukocyte values varied between 9.8 and 25.8 x 10 (9)/L. In women with PROM, CRP and leukocytes should not be measured routinely.