BACKGROUND Patients with metastatic melanoma to their regional lymph nodes have a poor prognosis despite lymphadenectomy. In an attempt to improve their survival, this feasibility study was undertaken. METHODS Twenty-two melanoma patients, who presented with enlarged regional lymph nodes, underwent therapeutic lymphadenectomy. They were found to have N2 nodal disease, with no evidence of distant metastases, i.e., advanced Stage III disease. One month after the lymphadenectomy, each patient received five autologous tumor vaccines. Each vaccine consisted of 20 x 10(6) irradiated autologous tumor cells (20,000 cGy) injected intradermally. The first two vaccines contained BCG and were given 1 week apart. The other three vaccines consisted of irradiated tumor cells only without BCG, administered over 2-, 4-, and 8- week intervals, respectively. Cyclophosphamide was administered intravenously as 300 mgm/m2 3 days prior to vaccines 1, 4, and 5 to reduce the population of T-suppressor cells. The patients were observed with no additional therapy. Three patients developed recurrences and these site were resected, and the patients were revaccinated in the same fashion utilizing the new tumor cells. RESULTS After a follow-up of 4-6 years, 15 patients (including 3 who were revaccinated) of the initial 22 patients (68.2%) are alive free of disease. CONCLUSIONS Adjuvant immunotherapy with irradiated autologous melanoma cells and low dose cyclophosphamide seemed to yield better relapse-free survival than the historically reported 10-25%.