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We evaluated interleukin‐6 (IL‐6) receptor‐α subunit (IL‐6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL‐6Rα receptor occupancy (RO) and C‐reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL‐6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL‐6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28‐joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL‐6Rα in vitro with 15‐ to 22‐fold higher affinity than tocilizumab, and inhibits IL‐6–mediated classical and trans signaling via membrane‐bound and soluble IL‐6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady‐state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28‐joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL‐6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements. [ABSTRACT FROM AUTHOR]