1. Morphine, DAMGE and U50,488H each inhibit the in vitro proliferative response of murine splenocytes to the mitogenic agents PMA or SEB. The kappa agonist U50,488H is much more potent than either of the mu-receptor agonists. The immunosuppressive activity of U50,488H is reversed by the opioid antagonists naloxone or norBNI. On the other hand, the immunomodulatory activity of morphine is reversed only by naloxone. 2. The mu-receptor agonists morphine and DAMGE also inhibit the development of an antibody response in vitro. Much more potent inhibitory activity was also observed for the kappa agonists U50,488H and U69,593. The delta agonist DPDPE failed to exert measurable immunomodulatory activity under these experimental conditions. 3. The immunosuppressive activity of the kappa agonists was reversed by both naloxone and norBNI. In addition, the activity of these opioid compounds exhibited stereospecificity. 4. Strain analysis has revealed the existence of two groups of mouse strains. The relatively sensitive mouse strains appear to include the BALB/c, C57BL/6 and B10.A(5R) strains. Four relatively less sensitive strains have also been identified. 5. Immunomodulatory activity has been detected for the kappa-selective agonists in the mu receptor-deficient strain CxBK/ByJ. Both mu and delta agonists fail to exert immunosuppressive activity in this mouse strain.