Aim: To evaluate the diagnostic value of interleukin-6 (IL-6) to predict the likelihood of neonatal sepsis in order to design an algorithm to decide antibiotic therapy. Methods: IL-6 and C-reactive protein (CRP) were determined in 42 newborns with clinical suspicion of infection. Newborns were classified as a confirmed, probable or no infection, based on the results of cultures, chest X-rays and the involvement of four or more clinical areas on a scale of eight. Samples for IL-6 were collected in the initial assessment and frozen until its determination at the end of the study. Blinded IL-6 measurements were performed using a rapid test. Receiver operator characteristics curves (ROC) for CRP and IL-6 versus infection (confirmed or probable) were determined. Results: Among the 42 cases included in the study 11 (26.2%) were classified as confirmed or probable infection. The area under curve (AUC) for IL-6 was 0.9, with a cut-off value of 53 pg/ml: sensitivity 90.91%, specificity 80%, positive predictive value (PPV) 62.5% and negative (NPV) 96% The level of IL-6 > 96 pg/ml and/or the combination of IL-6 > 53+CRP > 13.3 mg/l, were the markers that best predicted infection: specificity 100% and PPV: 100%. Conclusions: Assessment of IL-6 could allow withholding or early discontinuation of antibiotics in newborns with IL-6 < 54 pg/ml. In cases with IL-6 > 96 pg/ml and/or IL-6>53+CRP > 13.3, antibiotics should be started promptly, given the high likelihood of infection. Implementation of an algorithm based on the determination of IL-6 and CRP, in the initial assessment of the newborn with clinical suspicion of infection, could reduce unnecessary antibiotic therapy. (C) 2009 Asociacion Espanola de Pediatria. Published by Elsevier Espana, S.L. All rights reserved.