The main purpose of the present study was to determine whether specific lymphokines may be neurotrophic, by testing their effects on the survival of hippocampal neuronal cultures. Previous studies have shown that a variety of interleukins may be neurotrophic or neurotoxic, depending upon the culture conditions, as well as the concentration and time of exposure to the interleukins. The present results indicate that interleukins-4, -5, -7 and -8 significantly enhance neuronal survival of hippocampal cultures. These effects were concentration-dependent and reached maximal levels with concentrations of the lymphokines ranging from 500 to 1,000 ng/ml. With increased exposure to the lymphokines, the increase in neuronal survival compared to control untreated cultures persisted. Moreover, with IL-7, and particularly IL-8, this increased survival was more pronounced in the longer-term cultures. Thus, in the 7-day-old cultures, the magnitude of the increase in survival in the IL-8-treated cultures ranged from 93 to 123% compared to 56–68% in the 3-day-old cultures. In contrast, other lymphokines tested, interleukin-3 and -6, did not affect the survival of 1-day-old cultures and caused significant reductions in the longer-term cultures. Although the mechanism(s) of the neurotrophic effects of interleukins-4, -7 and -8 are not clear, an indirect effect mediated by proliferating glia in the treated cultures may be possible. Clearly, exposure to interleukins-4, -7 and -8 resulted in a marked increase in the number of astroglia and microglia compared to the control cultures, an effect that was amplified with increased time in vitro. The results exemplify the complexity of interactions that exists between immunomodulators and central neurons in vitro.