Trimetrexate glucuronate, a nonclassical antifolate, was administered to 14 patients with recurrent and progressive metastatic malignant melanoma. Thirteen patients were evaluable for response and toxicity. Five patients had received prior treatment consisting of immunotherapy (one patient), immunotherapy plus radiotherapy (one patient), radiotherapy (one patient), chemotherapy (one patient), or radiotherapy and chemotherapy (one patient). The starting dose of trimetrexate was 8 mg/m2 given as an intravenous bolus daily for 5 consecutive days of a 21-day cycle. Subsequent cycles of therapy were escalated by 25% based on individual patient tolerance. A median of two courses of trimetrexate was administered (range 1-4). No patient demonstrated a measurable objective response to this treatment regimen. Trimetrexate was well-tolerated; toxicity was mild and consisted primarily of myelosuppression or nausea and vomiting. At the dose level and schedule used in this study, trimetrexate was not effective for the treatment of disseminated malignant melanoma.