The influence of various modes of immunosuppression using cyclosporin A (CyA), corticosteroids (Cort), azathioprine (AZA), and antithymocyte globulin (ATG) alone or in combination with each other upon natural killer (NK) cell activity and antibody-dependent cellular cytotoxicity (ADCC) was assessed. CyA given alone did not influence either NK or ADCC activity; in contrast, the administration of Cort resulted in a significant decline (P less than 0.01) of ADCC but not of NK activity (P greater than 0.1). The combination of the two drugs led to a significant impairment of NK activity (P less than 0.01). The combination of AZA and Cort was found to produce an even more pronounced reduction in NK activity compared to both healthy controls (P less than 0.001) as well as patients from the CyA + Cort group (P less than 0.001). A similar decrease was found also after the addition of ATG to CyA + Cort (P less than 0.001, compared both with patients on CyA + Cort and with controls). In these instances, ADCC showed an overall similar pattern. We conclude that the administration of either CyA or Cort does not influence NK activity, while the combination of CyA with Cort and of AZA with Cort leads to a decrease in both NK and ADCC activities. The monotherapy with Cort only leads to a reduction of ADCC. These findings may explain the higher incidence of malignancies in patients undergoing combined immunosuppressive treatment.