ObjectiveTo investigate a possible short‐term dose‐response relationship of initial treatment with methotrexate (MTX) in monotherapy and combination therapy in recent‐onset rheumatoid arthritis (RA) patients.MethodsA systematic literature search was performed on trials and cohorts, including early, disease‐modifying antirheumatic drug (DMARD)–naive RA patients treated with MTX, with data on clinical results within 6 months from treatment start. Cohen's effect sizes were calculated for the Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate (ESR)/C‐reactive protein (CRP) level, and/or Disease Activity Score (DAS)/in 28 joints (DAS28) in 4 treatment groups: MTX monotherapy, or MTX in combination with synthetic (cs) DMARDs, biologic (b) DMARDs, or glucocorticoids. Random‐effects meta‐regression analyses were performed for each outcome, with treatment group as the predictor corrected for baseline HAQ or disease activity and assessment point.ResultsThirty‐one studies including 5,589 patients were included. The meta‐regression did not support higher effectiveness of increasing MTX dose in monotherapy. The number of treatment groups using combination therapy with csDMARDs was too small to perform meta‐regression analyses. In combination therapy with glucocorticoids, a higher MTX dose was associated with higher (worse) outcome HAQ, but not with DAS/DAS28 or ESR/CRP level. In combination therapy with bDMARDs, a higher MTX dose was associated with higher outcome HAQ and DAS/DAS28, but not with ESR/CRP level. All effect sizes were small.ConclusionIn DMARD‐naive, early RA patients who start MTX, either as monotherapy or in combination with bDMARDs or glucocorticoids, a higher initial dose of MTX was not associated with better clinical outcomes. This finding suggests that there is little short‐term gain from starting with high compared to low MTX doses.