Background: Methotrexate (MTX) remains the recommended first-line treatment for rheumatoid arthritis (RA); however, its response varies and is influenced by various factors. This study aimed to identify predictors of MTX monotherapy treatment success in an Indonesian cohort. Methods: This retrospective cohort study included newly diagnosed RA patients receiving MTX monotherapy. Treatment success was defined as achieving remission or low disease activity according to Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28-ESR) after 12 months of MTX therapy. The association between demographic, clinical, and laboratory factors and achieving therapy targets was evaluated using multivariate logistic regression analysis. Results: Among 254 subjects, 59.4% achieved treatment success with MTX monotherapy, with remission attained in 33% and low disease activity in 26.4%. Most subjects were female (95.7%) with a mean age of 48 ± 11 years. Multivariate analysis revealed that lower disease activity (OR 1.97; 95% CI [1.04–3.72]), normal ESR (OR 2.58; 95% CI [1.05–6.34]), normoweight (OR 2.55, 95% CI [1.45–4.49]), and tender joint count ≤ 5 (OR 2.45, 95% CI [1.31–4.58]) were significant predictors of treatment success. Conclusion: The rate of MTX monotherapy success in our study was 59.4%. Lower disease activity, normal ESR, normoweight, and fewer tender joints at baseline were significant predictors of treatment success. © The Author(s) 2024.