Various studies have shown that in vitro production of cytokines by leukocytes from the newborn are normal, decreased, or increased. We investigated the blood levels of tumor necrosis factor-alpha (TNF-alpha) interleukin-1 alpha, interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) simultaneously to assess the cytokine response to systemic infection during the neonatal period. One or more cytokine levels were elevated in all of the newborns with sepsis. Serum TNF levels in the newborns with sepsis were significantly higher than the two control groups (P < 0.002). Serum IL-6 levels in the study group were also found to be significantly higher than the control groups (P < 0.0004 for sepsis vs adult controls and P < 0.03 for sepsis vs newborn controls). We could not find statistically significant correlation between any of the cytokine levels, C-reactive protein, white blood cells, and platelet counts and the outcome. Gram-negative bacteria were the main causative agents in these patients, although one of them was infected with gram-positive bacteria, besides one premature infant (29 weeks) with Candida sepsis also had significantly elevated TNF, IL-1 beta, and IL-6 levels. Our data show that both mature and premature neonates were able to produce and significantly increase the blood levels of the cytokines in response to sepsis. Because the biologic relevance of cytokine levels is not known, further prospective and sequential studies on cytokine levels simultaneously and correlation with clinical parameters are needed to clarify the biological role of this important component of the host defense system.