In a prospective, open-label, 104-week study, patients who were infected with human immunodeficiency virus type 1 (virus load, <50 copies/mL) and who were receiving protease inhibitor-based therapy were randomly assigned to continue treatment with a protease inhibitor or to replace it with abacavir or efavirenz. Treatment failure, defined as virological failure (virus load, >500 copies/microL) or any clinical or biochemical adverse event with a grade of >or=3 (on the basis of the World Health Organization [WHO] or American Heart Association [AHA] scales), was the primary outcome measurement. Failure rates were more frequent in the group treated with protease inhibitors (P<.01), and there were no significant differences in the rate of treatment failure between the group treated with efavirenz and the group treated with abacavir. Tolerability was better in the groups treated with abacavir or with efavirenz versus those treated with protease inhibitors. Fewer patients who received efavirenz experienced viral rebound. Among all groups, the mean increase in the CD4 cell count was 131 cells/microL (P<.001), with no significant difference between groups. This switching strategy maintains optimal levels of virological suppression and may improve lipid profiles in most patients.