Persistency is the time from initiation to discontinuation of therapy. Previous research has described factors that affect the persistency of initial antiretroviral therapy (ART); however, the impact of persistency on clinical outcomes is unknown. A retrospective study was conducted of treatment-naive HIV patients initiating ART between January 1, 2000 and December 31, 2010 at an academic medical center. Descriptive statistics and Cox proportional hazards regression models with persistency as a time-varying covariate were fit for (1) immunologic failure (subsequent CD4 lower than initial CD4); (2) development of an opportunistic infection (OI) or malignancy; and (3) mortality. Analyses were repeated with an interaction term of persistency (per 180 days) and time (before and after 1 year of ART). Among 879 patients who started ART, the mean age was 38 years (±10) and most patients were racial/ethnic minority (59%), males (80%), and with baseline CD4 <200 cells/mm3 (52%). There were 100 deaths, 94 OIs/malignancy, and 183 immunologic failures; the mean persistency = 723 days. In multivariable modeling, increased persistency decreased the overall and long-term hazard for immunologic failure (0.84 per 180 additional days; 0.70-1.00; 0.045). Increased persistency exhibited a potential trend toward decreased hazard for the occurrence of OI/malignancy (0.91; 0.80-1.03; 0.124) overall and after 1 year. Persistency exhibited a trend toward less risk of mortality in the first year of ART (0.42; 0.17-1.06; 0.067). In this study of the relationship between initial ART persistency and clinical outcomes, increased persistency was associated with a decreased hazard for the development of immunologic failure, a trend toward a decreased hazard for OI/malignancy, and a trend toward a decreased risk of first year mortality. Given these findings, the relationship between persistency and clinical outcomes merits further study. © Copyright 2013, Mary Ann Liebert, Inc. 2013.