Objective: Whether the rate of HIV antiretroviral therapy (ART) persistence has improved over time in the United States is unknown. We examined ART persistence trends between 2001 and 2010, using non-HIV medications as a comparator. Methods: We conducted a retrospective cohort study using Medicaid claims. We defined persistence as the duration of treatment from the first to the last fill date before a 90-day permissible gap and used Kaplan-Meier curves and Cox proportional hazard models to assess crude and adjusted nonpersistence. The secular trends of ART persistence in 43 598 HIV patients were compared with the secular trends of persistence with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (ACEI/ARB), statins, and metformin in non-HIV-infected patients and subgroups of HIV patients who started these control medications while using ART. Results: Median time to ART nonpersistence increased from 23.9 months in 2001-2003 to 35.4 months in 2004-2006 and was not reached for those starting ART in 2007-2010. In adjusted models, ART initiators in 2007-2010 had 11% decreased hazard of nonpersistence compared with those who initiated in 2001-2003 (P < 0.001). For non-HIV patients initiating angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB), statins, and metformin, the hazard ratios for nonpersistence comparing 2007-2010 to 2001-2003 were 1.07, 0.94, and 1.02, respectively (all P < 0.001). For HIV patients initiating the three control medications, the hazard ratios of nonpersistence comparing 2007-2010 to 2001-2003 were 0.71, 0.65, and 0.63, respectively (all P < 0.001). Conclusion: Persistence with ART improved between 2001 and 2010. Persistence with control medications improved at a higher rate among HIV patients using ART than HIV-negative controls.