We assessed the impact of an efavirenz-containing regimen versus a protease inhibitor–containing regimen on quality of life, emotional status, and adherence of HIV-1–infected patients. In addition, we sought to define the adverse events associated with these treatments, with a special focus on central nervous system disorders in the efavirenz treatment group. This prospective, randomized, two-arm, controlled study included 100 patients for whom initial treatment with a protease inhibitor–containing regimen failed. Patients were randomized to start treatment with two nucleoside retrotranscriptase inhibitors plus efavirenz (group 1; 51 patients) or two nucleoside retrotranscriptase inhibitors plus one or more new protease inhibitors (group 2; 49 patients). Quality of life was assessed by a five-point item adapted from the HIV questionnaire of the Medical Outcomes Study, emotional status was evaluated by the Profile of Mood State questionnaire, and patients self-reported adherence. Data were analyzed by both an as-treated method and an intention-to-treat–last observation carried forward method. Patients in group 1 reported the following findings at week 4: dizziness (66%), abnormal dreaming (48%), light-headedness (37%), and difficulty sleeping (35%). At week 24, dizziness (13%;p< .001), abnormal dreaming (18%;p= .002), light-headedness (13%;p= .01), difficulty sleeping (7%;p= .001), and nervousness (13%;p= .01) decreased in these patients. Irritability, abnormal dreaming, and nervousness persisted at week 48 in 13%, 10%, and 8% of group 1 patients, respectively. Patients in group 2 reported the following findings at week 4: light-headedness (8%), dizziness (5%), difficulty sleeping (4%), nervousness (4%), and headaches (3%). Patients in group 2 reported the following findings at week 48: difficulty sleeping (4%), nervousness (3%), headaches (3%), and light-headedness (2%). In group 1, quality of life (p< .001) and emotional status (week 48;p= .004) improved, both of which were better than those in group 2 (p= .001). Both groups maintained high levels of medication adherence, and no significant differences in the number of patients who had viral loads of <200 copies/mL at week 48 were found (78% of group 1 patients vs. 85% of group 2 patients;p= not significant). At week 48, the mean CD4 cell count ± SD was 497 ± 224/mm3in group 1 and 539 ± 298/mm3in group 2 (p= not significant). Despite similar immunologic and virologic outcomes, a second-line efavirenz-containing regimen improved quality of life of HIV-1–infected patients compared with a second-line protease inhibitor–containing regimen. However, close follow-up of patients receiving treatment with efavirenz-based regimens is recommended, especially for those with previous emotional disturbances due to central nervous system disorders in the short term and those with persistence of a low percentage of these disorders in the long term.