In a randomized study 35 patients with advanced epithelial ovarian cancers with progressive disease after prior single alkylating agent or combination chemotherapy were treated with intermediate high dose methotrexate-citrovorum factor rescue alone or methotrexate-citrovorum factor rescue plus cyclophosphamide. Objective responses to 2nd-line chemotherapeutic regimens were observed. The objective response rate of 43% observed with the methotrexate-citrovorum factor plus cyclophosphamide treatment was superior to that achieved with methotrexate-citrovorum factor given alone. This combination of agents is the most effective 2nd-line chemotherapeutic regimen for ovarian cancer tested, and its possibilities as 1st-line therapy were discussed. After early dosage modifications, serious toxic side effects were rare in this group of patients who had extensive prior therapy.