Objectives To compare clinical characteristics and factors predictive of resistance to initial treatment with Methotrexate-folinic acid (MTX-FA) in women with low-risk gestational trophoblastic neoplasia (GTN). Design A retrospective study Setting A tertiary center Populations Patients diagnosed with low-risk GTN. Methods: Demographic data, disease characteristics, treatment response, toxicity and data of the subsequent pregnancy were collected and analyzed. Main outcome measures Groups of patients who were responsive or resistance to treatment were compared. Stepwise logistic regression analysis was used to identify factors predictive of resistance to Methotrexate chemotherapy. Results Totally, 113 patients were eligible for analysis. The primary remission rate was 55.8% with first-line MTX-FA. All others patients achieved remission by subsequent treatment with Actinomycin D or multiple-agents chemotherapy. Relapse of disease was found in 4.4% and the overall survival rate was 99.1%. Univariate analysis showed that pre-treatment serum hCG, neutrophil-to-lymphocyte ratio at baseline, and serum hCG ratio of the first three consecutive cycles (C) were significantly associated with resistance to MTX-FA. Independent factors that predict failure to respond to first-line MTX-FA were pre-treatment serum hCG ≥15,000 IU/L (OR 3.95; 95%CI = 1.48-10.52; p=0.006), a less than 4.8-fold reduction of serum hCG between cycle 1 and cycle 2 (C1/C2) (OR 4.08; 95%CI = 1.60-10.39; p=0.003), and a less than 7-fold reduction of serum hCG from cycle 2 to cycle 3 (C2/C3) (OR 10.15; 95%CI = 3.10-33.30; p<0.001). Conclusions First-line MTX-FA treatment is effective in 55.8% of patients. Pre-treatment serum hCG, and hCG ratio between consecutive treatment cycles predicts initial treatment failure.