An in vivo model for human melanoma was established with the growth of CR3 and DE5 human melanoma tumor cells following i.v. injection into C.B.-17 severe combined immunodeficient mice depleted of murine natural killer (NK) cells. The ability of human NK cells to mediate antitumor activity in vivo was investigated by evaluating the number of lung nodules and survival of mice given injections of human NK cells i.v. early after injection of CR3 tumor cells. Under these conditions, human NK cells effectively reduced lung nodule counts and prolonged survival when coinjected with interleukin 2 (IL-2). Multiple injections of IL-2 given during the first 16 h post-NK injection did not further enhance the tumor reduction. Significantly increased antitumor activity against CR3 tumor cells in vivo was observed in mice receiving NK cells coinjected with IL-2 and interleukin 12 (IL-12) in comparison to NK cells and IL-2 only. However, coinjection of IL-12 with human NK cells alone did not reduce the tumor burden. These results demonstrate the antitumor activity of human NK cells against human melanoma in severe combined immunodeficient mice and its augmentation by IL-2, alone or in combination with IL-12, suggesting that this model can be used to further investigate the interaction between human NK cells and human tumors.