Normal subjects (n = 11) had a mean circulating natural killer (NK) cell activity of 188 lytic units per 107 peripheral mononuclear blood leukocytes. This activity was significantly enhanced by in vitro incubation with 500 U of alpha-interferon (+207 lytic units). The mean NK activity of renal transplant recipients on azathioprine (n = 17) or on cyclosporine (n = 17) studied at various times after transplantation was significantly decreased, as was the ability of interferon to enhance NK activity. In the cyclosporine group, interferon could not enhance NK titers 1 to 6 weeks after transplantation when the patients were on the highest doses of cyclosporine (mean, 1,002 mg/day) or when they were viremic for cytomegalovirus. After 18 weeks, when the patients received 546 mg/day or when viremia was no longer detected, the ability of interferon to enhance NK activity was mnore normal. Cyclosporine and cytomegalovirus infection may have a greater effect on the action of interferon on NK activity than on the NK titer per se. This defect may diminish the reserve of NK cells and contribute to post-transplant immunosuppression.