Background Despite worldwide use of parenteral methotrexate (pMTX), health economic evidence for its use in Crohn's disease (CD) is limited. The low price of this generic drug has removed any commercial incentive to further invest in research. However, there is an unmet need for treatment of mild-to-moderate CD, since biological/targeted therapies are usually reserved for patients with more severe disease due to the higher costs of these treatments. Objective To evaluate the cost-effectiveness of pMTX compared to the standard of care (SOC, i.e., high doses of oral corticosteroids (hdCS) followed by gradual tapering) for the treatment of mild-to-moderate CD in the Czech Republic. Methods We developed a 3-year Markov model with a 1-week cycle length comprising five health states. The model projected quality-adjusted life-years (QALYs) and costs from the healthcare payers' perspective. Efficacy data were obtained from a systematic literature review of clinical trials and extrapolated using survival analysis. Results Over a 3-year time-horizon, pMTX yields additional 0.111 QALYs (1.798 vs. 1.687) at an additional cost of euro513 (euro3087 vs. euro2574), with an incremental deterministic (probabilistic) cost-effectiveness ratio of euro4627 (euro4742)/QALY, far below the willingness-to-pay (WTP) threshold (approximate to euro47,000/QALY). The probabilistic sensitivity analysis showed that the probability of pMTX being cost-effective was 100%. A one-way sensitivity and scenario analysis confirmed the robustness of the base-case result. Conclusion Parenteral MTX proved to be cost-effective in patients with mild-to-moderate CD. This is the first published cost-effectiveness analysis of pMTX for this indication. It also shows an example of a lack of valuation of generic therapy despite its cost-effectiveness and a clear benefit to the healthcare system.