© 2016, American College of Rheumatology Objective: To compare persistence and adherence to triple therapy with the nonbiologic disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), hydroxychloroquine, and sulfasalazine, versus a tumor necrosis factor inhibitor (TNFi) plus MTX in patients with rheumatoid arthritis (RA). Methods: Administrative and laboratory data were analyzed for US Veterans with RA initiating triple therapy or TNFi + MTX between January 2006 and December 2012. Treatment persistence 365 days postindex was calculated using 3 definitions. Definition 1 required no gap in therapy of ≥90 days for any drug in the original combination. Definition 2 required no added or switched DMARD, no decrease to nonbiologic DMARD monotherapy, and no termination of all DMARD therapies. Definition 3 was similar to definition 2 but allowed a switch to another drug within the same class. Adherence used a proportion of days covered of ≥80%. Propensity-weighted analysis with matched weights was used to balance covariates. Results: The analysis included 4,364 RA patients (TNFi + MTX, n = 3,204; triple therapy, n = 1,160). In propensity-weighted analysis, patients in the TNFi + MTX group were significantly more likely than patients in the triple therapy group to satisfy all persistence criteria in definition 1 (risk difference [RD] 13.1% [95% confidence interval (95% CI) 9.2–17.0]), definition 2 (RD 6.4% [95% CI 2.3–10.5]), and definition 3 (RD 9.5% [95% CI 5.5–13.6]). Patients in the TNFi + MTX group also exhibited higher adherence during the first year (RD 7.2% [95% CI 3.8–10.5]). Conclusion: US Veterans with RA were significantly more likely to be persistent and adherent to combination therapy with TNFi + MTX than triple therapy with nonbiologic DMARDs.