INTRODUCTION: Despite randomized controlled trials showing relatively comparable clinical outcomes with triple therapy (Triple; MTX, SSZ, HCQ) vs combination therapy with TNFi+MTX (TNF/MTX), the real-world experience comparing these strategies has not been well studied. METHODS: We evaluated discontinuation and clinical effectiveness of Triple vs TNFi/MTX therapy amongst RA patients in the Corrona registry. Propensity score matching (up to 1:3) was used to adjust for imbalances, with stratification by biologic-naïve vs biologic-experienced status. RESULTS: In biologic-naïve patients, 3926 TNF/MTX and 262 Triple patients, and 3365 TNF/MTX and 130 Triple biologic-experienced patients, were potentially eligible for analysis. Before matching, numerous factors were imbalanced, with Triple patients being older, with longer RA disease duration, lower RA disease activity, and more likely to have a history of malignancy and other comorbidities. After matching, almost all (93-98%) Triple patients could be matched to TNF/MTX patient(s), and cohort characteristics were generally well balanced. Discontinuation was greater in Triple patients referent to TNF/MTX (adjusted HR 2.17 [aHR], 95%CI 1.63-2.88 in biologic-naïve; aHR=1.51, 95%CI 1.06-2.15 in biologic-experienced). In biologic-naïve patients at 6 months, the proportion attaining low disease activity (TNF/MTX:49.2% vs. Triple:33.3% respectively) was significantly greater in the MTX/TNF group, as was mean change in CDAI (-9.3 vs. -5.5 units, 95% CI -1.5 to -6.1). Corresponding results in biologic-experienced patients numerically favored MTX/TNF over Triple but were not significant. CONCLUSION: Few patients receive Triple in the US. Drug persistence and clinical effectiveness outcomes were less favorable for Triple compared to TNF/MTX therapy.