Nevirapine (NVP)-based antiretroviral therapy continues to be used in some human immunodeficiency virus (HIV)-infected patients. Rilpivirine (RPV) could be used as an alternative to NVP. We studied the efficacy of RPV-based regimens as switch therapy.A randomized controlled noninferiority trial was conducted in HIV-infected patients who received NVP-based regimens and had undetectable plasma viral loads (VLs). Patients were randomized to a continuation arm (NVP was continued) or a switch arm (NVP was switched to RPV). Tenofovir disoproxil fumarate (TDF) plus lamivudine or emtricitabine were the backbone of the regimens. The primary endpoint was an HIV VL <40 copies/mL at week 48.A total of 106 patients were enrolled, 55 patients were in the continuation arm and 51 patients were in the switch arm. The mean (standard deviation) age was 49.1 (9.2) years and 51.9% were females. The median (interquartile range) baseline CD4 count was 561 (443-732) cells/mm. At week 48, 52 patients (94.6%) in the continuation arm and 50 patients (98.0%) in the switch arm had an HIV VL <40 copies/mL, with an efficacy difference of 3.5% (95% confidence interval [CI], -13.0 to 5.6; = .619). Decreases in total cholesterol and triglyceride were observed in the switch arm (-17.1 mg/dL, 95% CI = -29.7 to -4.4, = .008 and -36.0 mg/dL, 95% CI = -71.0 to -1.1, = .044, respectively).Switching from NVP to RPV can maintain virological suppression and decrease total cholesterol and triglyceride at week 48. In patients virologically suppressed with NVP-based regimens, RPV-based regimens can be a switch option.