Abstract Background This study sought to evaluate the efficacy and safety of tofacitinib in patients with rheumatoid arthritis with distinct treatment histories. Methods Pooled phase II/III trial data from patients who received tofacitinib 5 or 10 mg twice daily or placebo, as monotherapy or with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), were analyzed post hoc. Separate evaluations were conducted for populations with a prior inadequate response (IR) to: 1) non-methotrexate (MTX) csDMARDs only (non-MTX csDMARD-IR; n = 537); 2) MTX (MTX-IR; n = 3113); and 3) biologic (b)DMARDs (bDMARD-IR; n = 782). Efficacy outcomes included rates of response (American College of Rheumatology 20/50/70% response criteria) and remission (Disease Activity Score in 28 joints derived from 4 measures, erythrocyte sedimentation rate [DAS28-4(ESR)] < 2.6) at month 3, and changes from baseline in DAS28-4(ESR) and Health Assessment Questionnaire–Disability Index scores. Safety was assessed up to month 24. Results At month 3, efficacy was generally improved with tofacitinib (both doses) vs placebo in each population. Generally, efficacy outcomes with tofacitinib were numerically more favorable in non-MTX csDMARD-IR vs MTX-IR or bDMARD-IR patients. Over 24 months, crude incidence rates for adverse events (AEs), serious AEs, and discontinuations due to AEs were generally numerically lower in non-MTX csDMARD-IR and MTX-IR vs bDMARD-IR populations; rates for AEs of special interest were generally similar across populations. Conclusions Tofacitinib provided clinical benefit across patients with rheumatoid arthritis with a range of prior treatment experience but may have greater efficacy and an improved benefit/risk profile in those with fewer prior treatments. Trial registration NCT00147498/NCT00413660/NCT00550446/NCT00603512/NCT00687193/NCT00976599/NCT01359150/NCT00847613/NCT00814307/NCT00853385/NCT00960440/NCT01039688/NCT00856544.