The hypothesis that neuroendocrine stimulation after aversive handling can alter natural resistance was examined in the tail electroshock (TES) model, a procedure that can activate pituitary neuropeptide secretion. Immediately after a brief TES session, the resistance of DBA/2J mice was suppressed in proportion to the intensity of the shock. Initial suppression of the natural resistance was rapidly reversed in longer treatment protocols, and repeated aversive stimulation augmented the antitumor response, leaving the mice more resistant to lymphoma than unhandled animals. Corticosterone was released into the serum after all acute handling procedures, and hydrocortisone inoculation suppressed antitumor responses. However, serum corticosterone levels did not quantitatively correlate with the alterations in natural resistance. The observation that TES-induced suppression of natural resistance could be reversed by the opiate receptor antagonist naltrexone suggested that endogenous opiated released after TES stimulation were immunosuppressive.