The aim of this research was to assess the cost-effectiveness of TNF-α antagonist therapies, including etanercept, infliximab and adalimumab administered along with methotrexate as a 3-line treatment in active rheumatoid arthritis (RA) in Polish settings. Main outcome measure was quality-adjusted life-years gained (QALY). Analysis was based on the probabilistic discrete event simulation model over the time horizon of a patient’s lifetime. All costs were calculated from the public payers’ perspective (National Health Fund). Input data on patients\' baseline characteristics, present clinical practice and resources use HAQ and utility HAQ relations was obtained from Polish RA patients and in Polish clinical settings. To test the uncertainty of the model parameters, sensitivity analysis was performed. Treatments including TNF-α blockers are more effective and yet more expensive compared to standard DMARDs combinations. Lowest cost for a quality-adjusted life-year gained (ICER) was recorded for etanercept: 115 788.28 [zł/QALY]. The ICER value for infliximab was 134 877.45 [zł/QALY]. Adalimumab appears to be the worst choice because the ICER value for this comparison is 142 782.53 [zł/QALY] – much higher than for the previous two TNF-α inhibitors. Similar relations for early RA and late RA subpopulations were observed. Sensitivity analysis confirmed the robustness of the model assumptions and obtained results. Cost-utility analysis of TNF-α antagonists used for RA treatment in Poland shows that etanercept is the most cost-effective therapy from that group.