To investigate the immunomodulating properties of cis-diamminedichloroplatinum (II) (CDDP), we studied the drug's effects on natural killer (NK) lymphocyte cytotoxicity. i.p. injections of CDDP (2-6 mg/kg) into adult mice significantly enhanced cytolysis of YAC-1 and K562 targets mediated by peritoneal and spleen cells. Lysis of the NK-resistant targets P815, EL-4, MOT, and RAJI was not increased, nor was the lysis of a YAC variant which had been specifically rendered resistant to NK lysis. Activated cytotoxicity was first noted 24 h after injection and returned to baseline by 7 days. Although i.p. injection enhanced peritoneal and spleen cell lysis, i.v. injection only activated spleen cells. Two analogues of CDDP, carbo- and iproplatin, effectively enhanced NK activity, but transplatin had no effect. Activated effector cells were non-adherent to nylon wool and serum-coated plates; they co-separated with lymphocytes on Percoll gradients, and they expressed asialo GM1 determinants. Incubation of targets with CDDP for 1 or 18 h significantly increased their sensitivity to lysis by normal murine spleen cells. These data indicate that CDDP has potent effects on NK cytotoxicity.