OBJECTIVE To compare diagnostic accuracy in cord blood of interleukin-6 (IL-6) with C-reactive protein (CRP) as predictors of early-onset neonatal sepsis (EOS) in newborns with prenatal risk factors for infection. METHODS During 12 months, cord blood IL-6 and CRP were measured immediately after birth in neonates with prenatal risk factors of infection. The odds of developing sepsis based on IL-6 and CRP values were calculated using likelihood ratios (LR), and their accuracy as predictors was compared by binary logistic regression. Multivariable logistic regression analyses were performed to identify independent risk factors for sepsis. RESULTS Ten of 128 neonates (7.8%) were diagnosed with EOS confirmed with positive blood culture in five cases (3.9%). Cord blood IL-6 was a greater predictor of sepsis than CRP [ROC for IL-6 (0.88) vs. CRP (0.70)]. IL-6-positive and IL-6-negative LR [7.14 vs. -0.11] were superior to those calculated for CRP [2.86 vs. -0.51]. Chorioamnionitis and Apgar at 1 min were identified as independent risk factors for EOS. CONCLUSIONS Cord blood IL-6 showed superior LR than CRP; therefore, it is a better predictor to initiate treatment in neonates with prenatal infectious risk factors immediately after birth.