Indirect immunofluorescent (IF) tests were done on acetone-fixed imprints of 10 malignant melanomas with the use of sera from 48 patients with melanoma, 17 with other types of solid tumors, and 65 normal blood-bank donors. Only small differences in the percentage of positive reactions (36–47%) were obtained with the 3 groups of sera, and similar reactivity was observed with other malignant tumors. Fluorescein isothiocyanate-conjugated melanoma patients' sera and normal sera were tested on melanoma tumor imprints, and a significant number of positive reactions was noted in each group. Although positive reactivity was completely removed by absorption of sera with homogenized test tumor, intensity was not reduced after absorption with whole cells, which suggested that neither HL-A nor blood-group antigens were involved. The distribution of positive reactions in indirect IF tests, the results of blocking tests with conjugated sera, and the results of absorption studies with homologous tumor tissue suggested that cross-reactive antibodies to at least 2 different cytoplasmic antigens were present in the 3 groups of sera. Despite this qualitative similarity in reactivity, there were significant quantitative differences distinguishing melanoma patients from normal individuals. The mean antibody titer for melanoma patients was 310; for normal sera it was 18 (P ≤ 0.05). Sera from 8 melanoma patients with stage I (local) and stage II (regional) disease had a mean titer of 152 compared to a titer of 423 for 14 patients with stage III (metastatic) disease. This difference suggested a positive correlation between the titer of antibody and the presence of metastatic disease.