ObjectivesTo evaluate whether addition of low-moderate dose prednisone to methotrexate (MTX) treatment can alleviate common MTX side-effects in rheumatoid arthritis (RA) patients.MethodsWe performed a post-hoc analysis of the CAMERA-II trial which randomized (1:1) 236 early DMARD and prednisone naive RA patients to treatment with MTX + prednisone 10 mg daily, or MTX monotherapy during two years. MTX dose was increased using a treat-to-target approach. We used Generalized Estimating Equations to model the occurrence of common MTX side-effects and of any adverse event over time, controlling for disease activity and MTX dose over time and other possible predictors of adverse events. To assess whether a possible effect was prednisone-specific, we performed the same analysis in the U-ACT-EARLY trial, in which the addition of tocilizumab (TCZ) to MTX was compared to MTX monotherapy in a comparable setting.ResultsMTX side-effects were reported at 5.9% of visits in the prednisone-MTX group, compared to 11.2% in the MTX monotherapy group. After controlling for MTX dose and disease activity over time, treatment duration, age, sex, and baseline transaminase levels, addition of prednisone significantly decreased the occurrence of MTX side-effects (OR: 0.54, CI: 0.38–0.77,p= 0.001). Specifically, the occurrence of nausea (OR 0.46, CI: 0.26–0.83,p= 0.009)) and elevated ALT/AST (OR 0.29, CI: 0.17–0.49,p< 0.001) was decreased. There was a trend towards fewer overall adverse events in the prednisone-MTX arm (OR: 0.89, CI: 0.72–1.11,p= 0.30). No difference in MTX side-effects was found between TCZ-MTX and MTX monotherapy in U-ACT-EARLY (OR 1.05, CI: 0.61–1.80,p= 0.87).ConclusionAddition of 10 mg prednisone daily to MTX treatment in RA patients may ameliorate MTX side-effects, specifically nausea and elevated ALT/AST.Supplementary InformationThe online version contains supplementary material available at 10.1186/s41927-023-00331-0.