BACKGROUND: Randomized trials have demonstrated that the efficacy of anti-TNF agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are commonly prescribed with other disease modifying antirheumatic drugs (DMARDs) than MTX, however their effectiveness in combination with anti-TNF agents is not well established. OBJECTIVE: To compare the effectiveness of leflunomide (LEF) and other conventional DMARDs with MTX as co-therapy to anti-TNF agents in RA. METHODS: All patients on anti-TNF agents and conventional DMARDs within the SCQM-RA database were included (N=1218) and categorized according to the type of co-therapy into anti-TNF+MTX (N=842), anti-TNF+LEF (N=260) and anti-TNF+other DMARDs (N=116). Drug discontinuation rates and incidence of toxic side effects were analyzed using Cox proportional hazards models. Progression of radiographic damage, the evolution of functional disability and the improvement of RA disease activity were analyzed using longitudinal regression models, adjusting for potential confounders. RESULTS: The overall discontinuation rates of anti-TNF and conventional DMARD combination therapies were relatively high with a median survival of only 16 months (IQR: 10 - 37), but they did not differ between the three regimen (p=0.69). The progression of radiographic damage (p=0.77), functional disability (p=0.09) and RA disease activity (p=0.33) were also similar between the different regimen. In addition, no significant difference in the frequency of adverse events emerged. CONCLUSION: Overall these results suggest that LEF and potentially other conventional DMARDs offer an effective and safe alternative to MTX as co-therapy in combination with anti-TNF agents.