This study is to compare the remission and complication rates of actinomycin D (Act-D) and methotrexate-folinic acid (MTX-FA) as single-agent treatments of stage I, low-risk gestational trophoblastic neoplasia (GTN). From 1994 to 2005, all women with International Federation of Gynecology and Obstetrics stage I, low-risk GTN were randomly assigned to received either intravenous Act-D 10 μg/kg per day for 5 days every 2 weeks or intramuscular methotrexate 1 mg/kg per day on days 1, 3, 5, and 7 with intramuscular folinic acid 0.1 mg/kg per day on days 2, 4, 6, and 8 every 2 weeks. Forty-nine women met the eligibility criteria. Age, human chorionic gonadotropin level, and International Federation of Gynecology and Obstetrics score were similar in both treatment groups. Of the 22 women who received Act-D, 2 were lost to follow-up. Among the 27 women who received MTX-FA, 2 were lost to follow-up, and 6 had to switch to Act-D because of the rising levels of liver enzymes. All 20 women (100%) in the Act-D arm achieved remission compared with 14 (73.6%) in 19 women in the MTX-FA arm (P = 0.02). Mucositis and alopecia were reported more frequently in the Act-D group, whereas elevations of liver enzyme levels were more frequent in the MTX-FA group. Actinomycin D seems to be more effective than MTX-FA in the treatment of stage I, low-risk GTN. Larger multicenter randomized controlled trials should be conducted to establish the most appropriate regimen for these patients.