In two clinical trials the mouse antiidiotypic monoclonal antibody (MAb) MF11-30, which bears the internal image of human high-molecular-weight-melanoma-associated antigen (HMW-MAA) was administered by subcutaneous route without adjuvants to patients with stage IV malignant melanoma on day 0, 7, and 28. Additional injections were administered if anti-antiidiotypic antibodies were not found or their titer decreased. In the first phase I trial with 16 patients the initial dose was 0.5 mg per injection and escalated to 4 mg per injection. Neither toxicity nor allergic reactions were observed despite the development of anti-mouse Ig antibodies. Minor responses were observed in three patients. In a second clinical trial MAb MF11-30 was administered to 21 patients at a dose of 2 mg per injection, since this dose had been shown in the initial study to be effective in inducing anti-antiidiotypic antibodies. Two patients were inevaluable; in the remaining 19 patients, the average duration of treatment was 34 wk. In this trial as well, neither toxicity nor allergic reactions were observed. 17 of the 19 immunized patients increased the levels of anti-mouse Ig antibodies and 16 developed antibodies that inhibit the binding of antiidiotypic MAb MF11-30 to the immunizing anti-HMW-MAA MAb 225.28. One patient increased the level of anti-HMW-MAA antibodies. One patient achieved a complete remission with disappearance of multiple abdominal lymph nodes for a duration of 95 wk. Minor responses were observed in three patients. These results suggest that mouse antiidiotypic MAb that bear the internal image of HMW-MAA may be useful reagents to implement active specific immunotherapy in patients with melanoma.