In critically ill preterm infants, fungal infections produce significant morbidity and mortality. Human adult lymphocytes activated by interleukin-2(IL-2) inhibit the growth of the hyphal form of Candida albicans. We hypothesized that activated lymphocytes from infants with higher severity of illness scores would be less effective in suppressing candidal growth. Methods: Lymphocytes were isolated from adult peripheral blood and cord blood of term and preterm infants by differential centrifugation and placed in RPMI-1640 medium with IL-2 (1000 u/ml) for 5 days. The lymphocytes were then incubated with the hyphal form of C. albicans for 3 hrs. Growth inhibition of the fungal hyphae was assessed by [3H]uridine incorporation. Severity of illness was determined within the first 24 hrs of admission to the NICU by use of the Score for Neonatal Acute Physiology(SNAP). Results: Lymphocytes obtained from 36 preterm and term infants demonstrated less (P<0.05) growth inhibition of C. albicans than did lymphocytes from adult blood. In addition, cord blood from female infants had a greater (P<0.05) inhibitory effect than did that from male infants. An inverse relationship (r=-0.412; P<0.02) was found between SNAP and lymphocyte inhibition of candidal growth (i.e., infants with higher SNAPs had the least antifungal activity). Conclusion: We conclude that neonatal lymphocytes are deficient in anti-candidal activity compared to adult lymphocytes. Further, the most severely ill infants were the least capable of mounting effective lymphocyte mediated antifungal activity. This deficiency may contribute to the increased susceptibility to candidal infections in critically ill preterm infants. Supported by: AI-31127 and NR-00085.