Objective: Combination treatments for patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX) alone include the addition of a tumor necrosis factor inhibitor (TNFi) or the addition of sulfasalazine (SSZ) and hydroxychloroquine to MTX (triple therapy). We compared persistence and adherence rates between these 2 combination therapies in US veterans and report the reasons for discontinuation of combination treatment in these groups. Methods: Using Veteran's Affairs clinical and administrative data from 2006 to 2012, veterans with RA escalating treatment from MTX to MTX-TNFi or triple therapy were examined for a 12-month period after combination initiation. Persistence was defined as treatment without a ≥90-day gap in therapy. Adherence was calculated using the proportion of days covered ≥80% at 12 months. Matching weights–adjusted models were applied to more closely mimic randomization in this study. The reasons that patients discontinued their combination regimens were identified by chart abstraction. Results: Full persistence at 1 year was 45% in the MTX-TNFi patients (n = 2,125) and 18% in the triple therapy patients (n = 171) (P ' 0.001). Adherence was higher for the MTX-TNFi group (26%) than the triple therapy group (11%) (P ' 0.0001). The triple therapy group was associated with significantly more treatment discontinuation, which was most often due to adverse drug events from SSZ. Conclusion: Differences in persistence and adherence between the MTX-TNFi and triple therapy groups appear to be primarily related to adverse drug events that were most often attributed to SSZ.