Subungual melanoma is rare and represents only 1% to 3% of all diagnosed melanomas in Western countries. The tumor is frequently mistaken for a benign lesion and the delay in diagnosis and final treatment may be responsible for the high local recurrence rate and the low disease-free survival rate. From 1965 to 1982 the combined-modality therapy of amputation and adjuvant isolated regional perfusion with melphalan with or without dactinomycin was used in the treatment of 22 patients with subungual melanoma. Disease was staged according to the M. D. Anderson classification, as follows: stage I (primary melanoma), 11 patients; stage IIIA (in-transit metastases and/or satellitosis), three patients; stage IIIB (regional lymph nodes), seven patients; and stage IIIAB (in-transit metastases and/or satellitosis and regional lymph nodes), one patient. There were no cardiovascular complications and no treatment mortality. During a follow-up of at least 4.5 years, 12 patients (55%) developed distant metastases, including four patients with stage I disease (36%) and eight patients with stage III disease (73%). There were no locoregional recurrences. The median survival was three years (range, 0.5 to 12.5 years) and the overall five-year survival was 40%, with 56% of patients having stage I disease and 27% having stage III disease. The prognosis of subungual melanoma is determined by the stage of the disease. Isolated regional perfusion may prolong disease-free survival in patients with subungual melanoma compared with previously published data.