The clinical course of 61 patients with high-risk metastatic gestational trophoblastic disease was reviewed. Currently, 34 patients (56%) are alive and in complete remission. The survival rate after full-term pregnancy was significantly worse than after any other type of antecedent pregnancy. Analyzing survival by individual high-risk criteria revealed significantly improved survival for those patients with elevated beta-human chorionic gonadotropin titer alone when compared with all other high-risk criteria. Fifty-eight percent of patients (14 of 24) primarily treated with alternating-sequential therapy consisting of methotrexate and actinomycin-D experienced a complete remission. Of those patients primarily treated with methotrexate, actinomycin-D, and cyclophosphamide, 63% (20 of 32) achieved a complete remission. Treatment with second-line chemotherapy was largely unsuccessful. Aggressive early treatment is warranted in this group of patients, using multiagent chemotherapy. A search for newer more effective regimens should continue.