OBJECTIVES: Non-persistent use of any component of an antiretroviral (ARV) regimen can lead to viral replication and treatment resistance. We compared real-world persistence between HIV-1 infected patients receiving once-daily single tablet regimens (STRs) versus multiple-tablet regimens (MTRs) using 7-year history in a claims database.  In addition, we assessed whether initial MTR persistence predicted long-term persistence comparable to an STR.  METHODS: HIV-1 infected patients filling ARV prescriptions after a 90-day washout were identified in a large claims database (07/2006-03/2013). Index regimens were classified as STRs (1 pill daily) or MTRs (≥ 2 pills daily).  Persistence was measured as the time from starting the index regimen to the first 90-day prescription gap for any ARV in the index regimen, or to the first prescription for an ARV not in the index regimen. Persistence was compared between STRs and MTRs with a logrank test. Additionally, the subgroup persistent on MTRs for the first 6 months was compared to the full group receiving STRs and the subgroup persistent on STRs for the first 6 months. RESULTS: Among 3,590 patients who initiated ART, 1,909 (53%) patients initiated STRs; 1,681 (47%) initiated MTRs. Median persistence (95% confidence interval) was 36.5 (31.3, 38.9) months on STRs and 13.2 (11.9, 15.0) months on MTRs (Difference 23.3; P<0.001).Within the subgroups persistent for the first 6 months, median persistence on MTRs was 26.1 (24.2, 28.3) and on STRs was 47.6 (41.2, 54.3) months. Limiting the MTR analysis to those patients who had persistence ≥ 6 months still fell short of the overall STR persistence (P<0.001). CONCLUSIONS: Patients receiving an STR regimen had significantly longer median persistence, by almost two years, compared to those receiving MTRs.  Even those patients who persisted on an MTR for the first 6 months experienced shorter overall persistence than those receiving an STR.