Background: The purpose of this study was to determine the relationship between early onset sepsis and increased levels of C-reactive protein (CRP) and interleukin-6 (IL-6) in cord plasma. Methods: A prospective study was conducted in 141 premature infants delivered with gestational ages of 26-35 weeks. IL-6 and CPR were measured by enzyme-linked immunoassay in the cord plasma of the neonates. According to clinical, laboratory findings and blood culture results, newborn infants were allocated into four groups (A-D): documented early onset infection, clinical sepsis, possible infection, and control groups respectively. Results: Mean IL-6 levels in group A-D was 264, 212, 160, and 33.3 pg/ml respectively. Difference between groups was statistically significant (p=.002). With cut off point of 18 pg/ml, the sensitivity and specificity of IL-6 for diagnosis of early onset sepsis was 72% and 55% respectively. There was not significant difference between mean levels of CRP among groups (p=0.28). Conclusion: Having considered the relatively good sensitivity and moderate specificity of cord IL-6, using this test can be recommended as a useful detector of early onset sepsis and non-infected sick neonates.