OBJECTIVE To determine the optimal approach to first-line treatment for low-risk gestational trophoblastic neoplasia (GTN) using a cost analysis of 3 commonly used regimens. METHODS A decision tree of the 3 most commonly used first-line low-risk GTN treatment strategies was created, accounting for toxicities, response rates and need for second- or third-line therapy. These strategies included 8-day methotrexate (MTX)/folinic acid, weekly MTX, and pulsed actinomycin-D (act-D). Response rates, average number of cycles needed for remission, and toxicities were determined by review of the literature. Costs of each strategy were examined from a societal perspective, including the direct total treatment costs as well as the indirect lost labor production costs from work absences. Sensitivity analysis on these costs was performed using both deterministic and probabilistic cost-minimization models with the aid of decision tree software (TreeAge Pro 2011, TreeAge Inc., Williamstown, Massachusetts). RESULTS We found that 8-day MTX/folinic acid is the least expensive to society, followed by pulsed act-D ($4,867 vs. $6,111 average societal cost per cure, respectively), with act-D becoming more favorable only with act-D per-cycle cost <$231, or response rate to first-line therapy > 99%. Weekly MTX is the most expensive first-line treatment strategy to society ($9,089 average cost per cure), despite being least expensive to administer per cycle, based on lower first-line response rate. Absolute societal cost of each strategy is driven by the probability of needing expensive third-line multiagent chemotherapy, however relative cost differences are robust to sensitivity analysis over the reported range of cycle number and response rate for all therapies. CONCLUSIONS Based on similar efficacy and lower societal cost, we recommend 8-day MTX/folinic acid for first-line treatment of low-risk GTN.