From 1966-1982, 138 previously untreated patients with metastatic malignant gestational trophoblastic disease received primary chemotherapy at the Southeastern Regional Trophoblastic Disease Center. Fifty-six (41%) had poor-prognosis metastatic gestational trophoblastic disease, and 51 (91%) of these patients were initially treated with multiagent chemotherapy. Sustained remissions were achieved in 128 patients (93%). Patients who had metastatic involvement of more than one anatomic site, disease duration of greater than four months, antecedent nonmolar pregnancy, or clinicopathologic diagnosis of choriocarcinoma were at significantly increased risk for failure to achieve sustained remission compared with patients who lacked these clinical features. Initial human chorionic gonadotropin level and site of metastasis had no significant effect on survival in these previously untreated patients. Patients with disease duration of greater than four months who had an antecedent nonmolar pregnancy were at significantly increased risk, with only 12 of 20 (60%) surviving, versus all of 85 patients with short duration of disease and antecedent molar pregnancy, and 32 (94%) of 34 patients with other combinations of these factors (P less than .001). Initial therapy for patients with metastatic gestational trophoblastic disease should be selected on the basis of prognostic factors that predict a high probability of failure with single-agent chemotherapy alone. Patients with prolonged duration of disease and nonmolar antecedent gestation are at high risk for failure using traditional forms of methotrexate and actinomycin D-based combination chemotherapy.