Objective The objective was to predict insufficient response to 3 months methotrexate (MTX) in DMARD naïve rheumatoid arthritis patients. Methods A Multivariable logistic regression model of rheumatoid arthritis patients starting MTX was developed in a derivation cohort with 285 patients starting MTX in a clinical multicentre, stratified single-blinded trial, performed in seven secondary care clinics and a tertiary care clinic. The model was validated in a validation cohort with 102 patients starting MTX at a tertiary care clinic. Outcome was insufficient response (disease activity score (DAS)28 >3.2) after 3 months of MTX treatment. Clinical characteristics, lifestyle variables, genetic and metabolic biomarkers were determined at baseline in both cohorts. These variables were dichotomized and used to construct a multivariable prediction model with backward logistic regression analysis. Results The prediction model for insufficient response in the derivation cohort, included: DAS28>5.1, Health Assessment Questionnaire>0.6, current smoking, BMI>25 kg/m 2 , ABCB1 rs1045642 genotype, ABCC3 rs4793665 genotype, and erythrocyte-folate<750 nmol/L. In the derivation cohort, AUC of ROC curve was 0.80 (95%CI: 0.73–0.86), and 0.80 (95%CI: 0.69–0.91) in the validation cohort. Betas of the prediction model were transformed into total risk score (range 0–8). At cutoff of 4, probability for insufficient response was 44%. Sensitivity was 71%, specificity 72%, with positive and negative predictive value of 72% and 71%. Conclusions A prognostics prediction model for insufficient response to MTX in 2 prospective RA cohorts by combining genetic, metabolic, clinical and lifestyle variables was developed and validated. This model satisfactorily identified RA patients with high risk of insufficient response to MTX.