Aim We aimed to compare weekly methotrexate (MTX) regimen and methotrexate-folinic acid (MTX-FA) 8-day regimen in the first line treatment of low-risk gestational trophoblastic neoplasia (GTN). Methods The study included 73 patients with low-risk GTN according to FIGO risk score (FIGO risk score < 7). All patients received either weekly MTX (30-50 mg/m(2) intramuscular weekly) or MTX-FA 8-day (MTX 1 mg/kg IV on day 1, 3, 5, and 7, FA 15 mg orally on day 2, 4, 6, and 8 given 24 h after each MTX dose, every 14 days) regimens in the first-line treatment of low-risk GTN. The baseline clinicopathological characteristics and treatment outcomes were analyzed retrospectively. Results The median age of all patients was 29 (18-51) years, and the median FIGO risk score was 3 (1-6). Of the patients recruited, 53 received MTX-FA 8-day, and 20 had MTX weekly regimens. There was a significant difference between the two groups with respect to FIGO risk scores (3 [1-6] vs. 2 [1-5], p = 0.023, MTX-FA 8-day vs. MTX weekly, respectively). The complete response rate was significantly higher in MTX-FA 8-day group compared to MTX weekly group (83% [44/53] vs. 60% [12/20] p = 0.038). In univariate and multivariate regression analyses, only presence of lung metastasis was found to be an independent risk factor for treatment resistance (OR: 3.959, 95% CI 1.105-14.179, p = 0.035). Conclusion MTX-FA 8-day regimen is more effective than weekly MTX regimen in the first line treatment of low-risk GTN including patients even with higher FIGO risk scores. Treatment resistance may develop especially in patients with lung metastasis.