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To assess if smoking status at the time of commencing an anti-TNF-α agent for rheumatoid arthritis (RA) reduces the likelihood of achieving at least a moderate response on the European League Against Rheumatism (EULAR) response criteria at 3-month assessment.All patients with RA treated with their first anti-TNF-α agent at the Department of Rheumatology, Derby Hospital NHS Trust between April 2001 and October 2008 were included in this retrospective case control study. Information about age, gender, disease duration, body mass index, smoking status (current smoker, ex-smoker, and nonsmoker), comorbidities, oral prednisolone use, and 28 joint 4 variables disease activity score (DAS28) at the time of commencing an anti-TNF-α agent was recorded. Details of rheumatoid factor (RF) and past and present disease modifying antirheumatic drugs were recorded. A case control study was carried out to examine possible baseline predictors of treatment effects at the 3-month assessment.Results were available for 395 patients at 3-month assessment. According to the EULAR response criteria 42 patients failed to show at least a moderate response. After adjusting for confounders using multivariate analysis, current smoking at the time of commencing an anti-TNF-α agent reduced the chance of achieving at least a moderate response on the EULAR response criteria when compared with nonsmokers (aOR [95% CI] 0.20 [0.05–0.83], P = 0.03).RA patients who smoke are less likely to respond to an anti-TNF-α agent.