The efficacy of single agent chemotherapy with methotrexate in low risk gestational trophoblastic disease is well established, but efforts to reduce toxicity and patient time and cost continue. Twenty-five patients with nonmetastatic postmolar gestational trophoblastic disease were seen by the Division of Gynecologic Oncology at the University of South Florida between February 1986 and December 1991. Patients were treated with either weekly intramuscular methotrexate 40 mg/M2 (Group 1, n = 13) or alternating doses of intramuscular methotrexate 1 mg/kg and folinic acid 0.1 mg/kg over eight consecutive days with an eight- day interval (Group 2, n = 12). Patient age, body weight and pre-treatment beta-hCG values were similar in the two groups. One patient defaulted from treatment and was lost to follow-up. All other patients were cured. Complete remission was achieved with primary chemotherapy in nine (69%) patients in Group 1 and nine (75%) in Group 2. All patients with pre-treatment beta-hCG of 650 mIU/ml or less responded to primary therapy whereas 50% of those with higher levels required second-line therapy. When secondary and tertiary treatment were included, the duration of treatment was similar in both groups. Remission was achieved at significantly lower levels of methotrexate in group 1 patients (p < 0.001). No major toxicities occurred. Side effects were gastrointestinal and myelosuppressive and occurred in 2.5% and 15.6% of treatment cycles in Groups 1 and 2, respectively (p < 0.01). Weekly methotrexate is an equally effective and less toxic regimen than eight-day methotrexate-folinic acid in nonmetastatic postmolar gestational trophoblastic disease.