To evaluate the relationship between tumor burden and circulating immune complexes (IC) in malignant melanoma, we tested sera collected serially from 15 normal donors and 53 patients. Forty-eight of these had Stage III or IV disease at the outset of the study. The median survival time (MST) of ten patients with Stage IV disease whose sera contained C1q-binding IC at the outset of the study was 4.7 months; the MST of the 25 Stage IV patients whose sera were initially free of IC by this test was 8.65 months (p less than 0.02). C1q-binding IC were not found in the initial serum samples from 13 patients with Stage III or 5 patients with Stage I disease. Abnormal C1q binding tests were measured in 4 of 67 sera (6%) from 13 patients who remained free of evident tumor for up to 41 months. IC were detected in 13 of 39 sera (33%) from 19 patients with progressively growing tumors and in 21 of 68 sera (31%) from 21 patients who were initially free of disease but developed recurrences later, or who had significant remissions of variable duration during follow-up. The MST of 31 patients whose serial serum samples remained free of C1q-binding IC was 15.8 months. Twelve patients whose sera were initially free of circulating IC later developed abnormal serum C1q-binding levels. Their MST was 10.3 months. The MST of ten patients with persistently abnormal serum IC levels was 4.7 months. C1q-binding IC were reciprocally related to the presence of complement-dependent antibodies, cytotoxic for cultured allogeneic malignant melanoma cells in sera from 29 of these patients (r = -0.491;p = 0.003). These results suggest that the appearance of circulating C1q-binding IC is pathophysiologically important in malignant melanoma. Measurement of C1q-binding IC may be useful in assigning prognosis in this disease.