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Background: Policy makers increasingly emphasize their need for information based economic outcomes to make reimbursement decisions. Objective: This analysis evaluates the cost-effectiveness of etanercept, infliximab and adalimumab in rheumatoid arthritis (RA)patients previously failing two disease-modifying anti-rheumatic drugs (DMARDs), versus traditional DMARDs. Adding rituximab after the failure of first-line tumor necrosis was also analyzed. Methods: Chinese unit costs and treatment sequences from a lifetime perspective were implemented. A mathematical model with 6-monthly cycle and synthesizing data with clinical trial and published literatures, and simulated hypothetical cohorts with moderate to severe RA. Switching to the next treatment is driven by the withdrawl probability of current treatment. The primary outcome measure-Quality-adjusted life years (QALYs)-was mapped from disease severity (HAQ scores). Primary analysis includes drug and monitoring costs, and other direct costs. Probabilistic sensitivity and one-way analyses were performed. Results: Treatment sequences that included TNF antagonists and rituximab produced a greater number of QALY than conventional DMARDs alone and TNF antagonists plus DMARDs. Etanercept, infliximab and adalimumab gained 8.22, 7.14 and 8.06 and 9.04, 8.15 and 8.94 QALYs with or without rituximab, and the cost were $208,733.8, $49,519.9 and $149,277.6 and $234,895.5, $81,982.2 and $177,441.4, respectively. In comparison with tDMARD, the incremental cost-effectiveness ratios (ICERs) for etanercept, infliximab and adalimumab with or without rituximab are $77,357.7, $26,562.4 and $57,838.4 per QALY and $66,422.9, $28,780.6 and $50,937.6 per QALY, respectively. Under the willingness to pay threshold was 3×the per capita GDP of China, no biotherapy was cost-effective. When 3×the per capita GDP of Shanghai used as the threshold, infliximab + rituximab could yield nearly 90％ cost-effective simulations in probabilistic sensitivity analysis. Conclusion: tDMARD was the cost-effective alternative option in the Chinese healthcare setting. In some relatively developed regions in China, infliximab + rituximab may be a favorable cost-effective alternative option for moderate to severe RA.