OBJECTIVES:  No guidelines are available for selecting a particular biologic agent for Rheumatoid Arthritis (RA) treatment. We conducted a cost-utility analysis to compare rituximab and three tumor necrosis factor inhibitors (anti-TNF) (adalimumab, etanercept, and infliximab) used as second-line therapy based on a “real world” data from Montreal, Quebec, Canada. METHODS: Four two-state (e.g., "on second-line treatment" and "after failing second-line treatment") Markov models were developed with TreeAge software to reproduce the 6-years-long course of patients treated either with adalimumab, etanercept, infliximab or rituximab. We included a cohort of RA patients registered in a clinical RHUMADATA® registry, who failed first-line therapy with an anti-TNF and were prescribed either rituximab, or one out three anti-TNFs of interest as a second-line biologic agent between January 1, 2007 and January 1, 2013. Baseline patient characteristics, transition probabilities, cost and treatment effectiveness were estimated for each group of patients based on the data from the registry. Transition probabilities for rituximab and combined anti-TNFs were obtained from Kaplan-Meier survival estimates of the 6-year drug retention rates. Unit costs (2016 CAD) from the province of Quebec were applied to value RA-related healthcare resources used (e.g., biologic agent and rheumatologist visits costs) measured on an item-by-item basis. Treatment effectiveness was expressed in QALYs gained calculated from HAQ scores over the follow-up time. Cost and effectiveness were discounted at 5% rate. RESULTS:  Overall, 119 patients were included. Over 6 year follow-up, rituximab as a second-line treatment was associated with cost of $74,472 and effectiveness of 3.88 QALYs gained and was dominant over treatment with adalimumab, etanercept, and infliximab, which were associated with cost of $90,738, $91,362 and $107,010, and effectiveness of 3.83, 3.54 and 3.27QALYs gained, respectively. CONCLUSIONS: Based on results of this analysis, over 6-year follow-up, the second-line rituximab therapy tends to be more effective and less costly than the 3 anti-TNFs.