The continuous infusion of the opioid peptide beta-endorphin prolongs skin allograft survival in mice, while the opiate receptor antagonist naloxone, administered together with the opioid at the time of transplantation, abolishes the effect of the opioid. Consistently, naloxone, when given alone at the time of transplantation, but not later, accelerates graft rejection and increases splenocyte IL-2 and interferon-gamma (IFN-gamma) production. Splenocyte beta-endorphin concentrations are lower in transplanted animals. The effects of exogenous beta-endorphin and naloxone suggest that the endogenous opioid peptide beta-endorphin exerts a tonic inhibitory effect over early events of T cell-mediated immune responses in vivo. The effects of beta-endorphin and naloxone are consistent with the previously shown role of the opioid system in the modulation of the Th1/Th2 cytokine pattern.