Introduction: Methotrexate and Actinomycin-D are still used for low risk gestational trophoblastic neoplasia (GTN). The aim of this study was to compare the efficacy and side effects of pulsed Actinomycin-D (ACT-D) and Methotrexate-Folinic Acid (MTX-FA) for Stage I, low-risk gestational trophoblastic neoplasia (GTN).Methods: This single-blind randomized clinical trial was conducted on 64 patients with stage I, low-risk GTN referred to gynecological oncology clinic of Tabriz University of Medical Sciences, Iran during 2011 and 2012. 32 patients were randomly assigned to receive a pulsed intravenous bolus of ACT-D 1.25 mg/m2 every 2 weeks and 32 patients received an intramuscular Methotrexate 1mg/kg per day on days 1,3,5,and 7 with intramuscular Folinic Acid 0.1 ml/kg per day on days 2, 4, 6, and 8. Data were analyzed using SPSS software (version 16) and Fisher exact test, Mann-Whitney U test, independent t-test and chi-square test. P value less than 0.05 was considered significant.Results: Response to treatment rate were 61.3% (19 patients) for MTX-FA group and 84.85% (28 patients) for ACT-D group (p=0.032). The risk of treatment failure with MTX-FA was 72 times more than ACT-D (p=0.032). The interval between drug administration and response was shorter with ACT-D in compare with MTX-FA (p<0.001). Drug toxicity necessitating changes in chemotherapy was reported in one out of 33 patients only in MTX-FA group. MTX-FA was more cost-effect regimen than ACT-D (p<0.001).Conclusion: Pulsed ACT-D may be an appropriate option as a first-line chemotherapy agent for patients with stage I, low-risk GTN.