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Complement-dependent cytotoxicity against melanoma cells was demonstrated with a microassay in sera from melanoma patients. The response was tumor-specific and histologic type-specific since 16 out of 52 (30%) melanoma patient sera taken before surgery reacted against melanoma cells, whereas 3 out of 43 (7%) control sera, collected from patients with unrelated tumors and from cancer-free individuals, were positive. The serum activity correlated with the clinical stage of the disease since it was detected in 15 out of 40 patients with stage I and II tumors and in 1 of the 12 patients in stage III. Twelve melanoma patients, clinically tumor-free for 1 to 4 years after surgery, showed no humoral cytotoxicity. A follow-up study of 13 melanoma patients revealed that the cytotoxicity appeared 7-10 days after radical removal of the tumor and that it disappeared if there was no recurrence. The histologic type-specificity was further tested by assaying sera from 16 melanoma and 10 breast-cancer patients simultaneously on both melanoma and breast-cancer cells; a positive reaction was observed in 6 cases of melanoma and in 5 of breast cancer on homologous cells only, in 1 case on the opposite type of cells, and in 3 cases on both types of tumor cells.