Alternating 5-day chemotherapy with methotrexate and dactinomycin as primary therapy for nonmetastatic gestational trophoblastic disease was studied in nine patients. The complete response rate was 100% with follow-up of a median of 80 months. Stomatitis was universal but rarely prevented oral alimentation or delayed therapy. Overall, 94% of toxicity was mild or moderate in severity and all toxicity was reversible. This alternating non-cross resistant regimen, reported in a total of 40 patients in the literature, is the only regimen to result in a 100% response rate. This response rate is statistically improved when compared to historical controls receiving methotrexate/folinic acid or pulse dactinomycin. No patients required hysterectomy for disease control. Cooperative prospective phase III studies are needed to determine the efficacy and toxicity of current regimens.