Opioid peptides affect different immune functions. We present evidence that these effects could be mediated by the modulation of Th1/Th2 cytokine production. The acute and chronic treatment with the opioid receptor antagonist naloxone decreased the production of IL-4 by splenocytes of C57BL/6 and Balb/cJ mice, that present a Th1/Th2 dominance, respectively, immunized with the protein antigen KLH. In contrast, IL-2 and IFN-gamma levels were increased after naloxone treatment. These results indicate that naloxone increases Th1 and decreases Th2 cytokine production. Moreover in C57BL/6 mice, naloxone treatment was able to accelerate skin-graft rejection, a Th1-mediated phenomenon, by increasing Th1 cytokine production. The effect of naloxone could be ascribed to the removal of the regulatory effects exerted by endogenous opioid peptides, which could activate Th2 and suppress Th1 cytokines.