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There is limited information about the factors related with the development of long-term permanent work disability (PWD) in rheumatoid arthritis (RA) treated with a combination of conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDs).The aim of this study was to evaluate incidence and factors associated with the development of PWD in RA treated with combination therapy using conventional synthetic cs-DMARDs.We assessed in multivariate models the effect of clinical and demographic factors in the development of PWD in a long-term retrospective cohort of 180 workers with RA who were treated with a combination of cs-DMARDs.Incidence rates of PWD were 2.2% at 1 year, 7.7% at 5 years, 24.9% at 10 years, 34.9% at 15 years, and 45% at 20 years. In the adjusted Cox regression analysis, factors associated with PWD development were the first failure with combination of cs-DMARDs (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.05–5.46; P = 0.03), poor functioning at time of cohort onset (HR, 2.2; 95% CI, 1.05–4.70; P = 0.03), and requirement for joint replacement (HR, 3.3; 95% CI, 1.28–8.79; P = 0.01).Around 25% of workers with combination therapy with cs-DMARDs developed PWD in 10 years following the diagnosis of RA. Some factors increase the risk of disability. Permanent work disability generates a relevant society burden and increases health care costs. Therefore, indicators predicting failure of combination therapies with cs-DMARDs might provide clinicians of useful tools for modifying treatments avoiding the disease progression.