The therapy of rheumatoid arthritis (RA) was advanced by biological agents, yet costly. This study aims to identify the effective threshold dose of etanercept (ENT) and cost-effectiveness in methotrexate (MTX)-resistant RA in real world. Eligible patients had an inadequate response (DAS28-ESR > 3.2) to initial MTX monotherapy, and subsequently received etanercept. The effective cut-off value of cumulative dose was identified to maintain remission response (DAS28-ESR < 2.6) at month 24 by using restricted cubic splines. Remission rate, low disease activity (LDA) rate, glucocorticoid exposure, safety, and cost-effectiveness were compared between the saturated and non-saturated dose groups divided by the cut-off dose. Seventy-eight (14.2%) of 549 enrolled patients were eligible, and 72 patients completed follow-up. The 2-year cumulative cut-off dose that maintained remission response at 24months was 1975mg. And the recommended threshold dosing strategy of etanercept was twice weekly (BIW) for the first 6months, every week (QW) for the next 6months, and every 2weeks (Q2W) and every month (QM) for the second year. Greater net changes in DAS28-ESR score were observed in the ENT saturated dose group than in the non-saturated dose group (average change 0.569, 95%CI 0.236-0.901, p = 0.001). The proportion of patients achieving remission (27.8% vs 72.2%, p < 0.001) and LDA (58.3% vs 83.3%, p = 0.020) in the non-saturated group was both significantly lower than that in the saturated group at 24months. The incremental cost-effectiveness ratio of the saturated group referred to the non-saturated group was 5791.2 $/QALY. In refractory RA patients, the effective cumulative cut-off dose of etanercept for sustained remission at 24months was calculated as 1975mg, and receiving saturated dose was more effective and cost-effective than with non-saturated dose. Key Points • The effective cumulative cut-off dose of etanercept for sustained remission at 24months in RA patients is calculated as 1975mg. • Receiving saturated dose of etanercept is more effective and cost-effective than with non-saturated dose in refractory RA patients.