Severe deficiencies of protein C, a pivotal coagulation-regulatory protein, have been reported in neonates as an apparently transient condition. In this prospective study, cord blood was collected at 193 deliveries and assays of protein C were correlated with clinical status, other coagulation results, and outcome. Protein C levels of less than 0.1 unit/ml were found most frequently in preterm infants with respiratory distress, infants of diabetic mothers, and infants of twin gestations. Levels of protein C correlated with levels of factor VIII activity but did not correlate with markers of consumptive coagulopathy. A protein C level less than 0.1 unit/ml was significantly correlated with the subsequent onset of thrombosis, even when the effects of gestational age and birth weight were excluded. Low cord blood levels of protein C may reflect delayed maturation or increased turnover in certain infants and appear to convey an independent risk of thrombosis, but the critical concentration of protein C necessary to maintain neonatal hemostasis is not known.