This study examined factors associated with persistence (time from initiation to discontinuation of treatment) on initial antiretroviral (ARV) therapy in commercially insured HIV patients in the United States, a population not well researched. This retrospective analysis of US health insurance claims data from 1 January 2003 to 30 June 2008 included treatment-naive patients aged 18-65 years with an HIV diagnosis receiving ARV therapy consisting of at least two individual nucleoside reverse transcriptase inhibitors (NRTIs) or one fixed-dose combination NRTI, plus at least one nonnucleoside reverse transcriptase inhibitor (NNRTI) or one protease inhibitor (PI), with or without ritonavir. Descriptive statistics, Kaplan-Meier survival estimation, and Cox proportional hazards regression models were completed. Patients were considered persistent until any component of the regimen was modified or there was a gap in treatment >90 days. A total of 2460 patients met full inclusion criteria (1388 NNRTI and 1072 PI). Mean (SD) time to discontinuation for NNRTI- vs PI-based regimens was 370 (346) vs 295 (338) days (p<0.001). Female sex, substance use, low comorbidity score, index year before 2007, geographical region, and taking a lopinavir/ritonavir regimen predicted discontinuation. Relative to NNRTI-based regimens, PI-based regimens demonstrated a greater risk of discontinuation (hazard ratio [HR], 1.32; p<0.001). The fixed-dose efavirenz/emtricitabine/tenofovir combination yielded the lowest risk of discontinuation (HR, 0.39; p<0.001). HIV treatment persistence was longer with NNRTI-based regimens than PI-based regimens. The fixed-dose regimen of once-daily efavirenz/emtricitabine/tenofovir had the lowest risk of discontinuation.