Cocaine has multiple immunomodulatory effects, including the ability to influence cytokine release in immunoeffector cells. Little is known, however, regarding the effects of cocaine on cytokine production by human peripheral blood lymphocytes (PBL). The effect of cocaine on PBL cytokine profiles and the molecular mechanisms responsible for the modulation of cytokine mRNA expression were investigated. To evaluate the effects of cocaine on cytokine production, conditioned supernatant from IL-2-stimulated PBL was evaluated by cytokine-specific ELISA (IL-4, IL-5, IL-8, IL-10, IFN-gamma, and TGF-beta) following in vitro cocaine exposure. Cocaine abrogated the IL-2-induced production of IFN-gamma and IL-8 in a dose-responsive manner. Cocaine also decreased PBL IFN-gamma and IL-8 mRNA expression as determined by Northern blot and slot blot analysis. Cocaine did not affect the stability of the IFN-gamma and IL-8 mRNA. Nuclear run-on assays revealed that cocaine down-regulated the rate of IFN-gamma and IL-8 transcription. These findings suggest that the immunomodulatory effects of cocaine may be mediated, in part, by modification of lymphocyte cytokine production.