Switching antiretroviral therapy has been shown as safe and effective, but its impact on health-related quality of life (HRQL) was rarely measured. Our objective was to assess changes in HRQL after switching to an non-nucleoside reverse transcriptase inhibitors (NNRTI) containing regimen among NNRTI-naive HIV-infected patients with viral load (VL) <500 copies/mL. In this prospective observational study, the Hospital Anxiety and Depression, Symptoms checklist, specific World Health Organization Quality of Life (WHOQoL) and generic SF-12v2 HRQL questionnaires were used to assess anxiety, depression, symptoms, and HRQL at baseline and months 1 (M1), 6 (M6), and 12 (M12). The statistical significance of changes in the frequency of anxiety and depression was determined with the McNemar test. Mean changes in the number of symptoms and in HRQL scores were compared using Wilcoxon's paired test. Data were available for 239 patients at baseline (162 with a switch to nevirapine) and for 164 patients at M6. The median age of the patients was 42 years and 67% of patients were male. The proportion of anxious patients diminished at M6 (11%, P=0.02) but not yet at M1. There was no change in the frequency of depression. Significant reductions (p<0.01) were observed at M6 in the mean number of all symptoms (-3.3), lipodystrophy symptoms (-0.8), other symptoms (-2.5), bothersome symptoms (-1.7), bothersome lipodystrophy symptoms (-0.4), and bothersome other symptoms (-1.3). HRQL as assessed with WHOQoL, improved in the physical, independence, and spirituality domains, with a small effect sizes at M6. Both for symptoms and HRQL, these changes were already significant at M1 and persisted at M12. This study shows that in patients with controlled VL, switching to an NNRTI regimen was associated with less anxiety, fewer perceived symptoms, and a small improvement in HRQL, while maintaining virological suppression.