Current smoking reduces clinical response to several disease-modifying antirheumatic drugs (DMARDs). It is unknown if this is also the case for prednisone. We aimed to determine whether current smoking affects the clinical response to concomitant prednisone in a methotrexate (MTX)-based treatment strategy.In the CAMERA-II trial, early rheumatoid arthritis (RA) patients initiated an MTX-based strategy and were randomized to concomitant prednisone (MTX+pred) or placebo (MTX+plac) for 24 months. Linear mixed modelling was performed with disease activity score assessing 28 joints (DAS28) as dependent variable and strategy group and current smoking status as independent variables, correcting for relevant covariates. The interaction between current smoking and strategy was tested to find out whether the impact of current smoking on clinical response was different between the strategy groups with prednisone or placebo.Current smoking was significantly associated with higher DAS28 over time (mean difference with non-smokers 0.57 (95% confidence interval 0.22 to 0.92), p<0.01). This association was not different between the strategy groups with prednisone or placebo (p=0.73). This negative effect of current smoking on DAS28 was dose dependent.Current smoking in early RA patients significantly reduces the clinical effect of an MTX-based strategy, independent of whether concomitant prednisone is used or not. This effect is dose dependent.