Estrogen receptor (ER) positivity demonstrated in malignant melanomas by histochemical and biochemical assays suggested the possibility of hormonal management and improved prognosis as for breast carcinoma patients. We studied the ER status of 5 primary and 28 metastatic malignant melanomas with a commercial immunohistochemical kit (ER-ICA monoclonal), that utilizes monoclonal anti-ER and a peroxidase-antiperoxidase technique, and by a histochemical method using fluorescein-conjugated estradiol (Fluoro-Cep Estrogen assay), on frozen sections. In addition, we conducted a biochemical assay [dextran-coated charcoal cytosolic assay (DCC)] in 16 cases. All 33 cases were ER negative by ER-ICA and Fluoro-Cep: 11 biochemical assays were negative (less than 3 fmol ER/mg protein), four were in the borderline range (3 to 10 fmol ER/mg protein), and one was positive (greater than 10 fmol ER/mg protein) at 11 fmol. The melanomas in 97% of the cases we studied were ER negative by two or three different assays. Low-level estrogen binding of MM tissues may be the result of interactions other than with Type I true ER. The low frequency of ER positivity of malignant melanomas appears to preclude the clinical use of ER status as an indicator for response to hormonal manipulation in patients with malignant melanoma.