The comparative systemic toxicity of methotrexate (MTX) with citrovorum factor rescue (CF), MTX alone and actinomycin-D (Act-D) in the treatment of gestational trophoblastic neoplasms (GTN) was evaluated in the present study. Treatment with MTX-CF was associated with only a 4% incidence (1 of 25 patients) of hepatic and/or hematologic toxicity and total absence of either a generalized rash or marked alopecia. In contrast, both MTX alone and Act-D were associated with a 48% incidence (12 of 25 patients) of hepatic and/or hematologic toxicity. Actinomycin-D also induced a generalized rash and marked alopecia in 24% (6 of 25 patients) and 52% (13 of 25 patients) of the patients respectively. We found that MTX-CF is the least toxic single agent chemotherapeutic regimen in the management of GTN.