While patients with melanoma are known to produce antibodies against melanoma cells, the tumor specificity of these reactions has not been well documented. Using the sensitive mixed hemadsorption assay we have identified antibody against one or more of nine different cultured melanoma cell lines in only nine of 48 patients with melanoma. Reactivity against melanoma cell lines was seen only in females, 9/27 versus 0/21 males. The strongest melanoma reactivity was seen in sera which also contained lymphocytotoxic antibody. The reactivity was not melanoma specific because it could be removed by absorption either with pooled platelets, nonmelanoma tumor cells or in two cases, by both. We conclude that the occurrence of specific antimelanoma antibodies against common or shared surface melanoma associated antigens is an uncommon event in melanoma patients not receiving specific active immunotherapy. The clinical significance of the observed reactivity and whether it is directed against cancer associated determinants, fetal antigens, or normal tissue or histocompatibility antigens requires further study.