Background. Atazanavir is a once-daily protease inhibitor (PI) for the treatment of human immunodeficiency virus (HIV) infection that has previously been studied in cohorts of treatment-naive and treatment-experienced patients. Limited data are available on the usefulness of switching from a PI-based regimen to a regimen based on a different PI, such as atazanavir, in HIV-infected patients experiencing virologic suppression but seeking regimen simplification. Methods. The Switch to Another Protease Inhibitor (SWAN) study was a 48-week, open-label trial involving HIV-positive patients with virologic suppression who were receiving stable PI-based regimens (with or without ritonavir). Patients were randomized 2 : 1 to switch to atazanavir (400 mg per day)—or, if they were receiving tenofovir, to atazanavir-ritonavir (300/100 mg per day)—or to continue to receive their existing PI. The proportion of patients who experienced virologic rebound (defined as an HIV RNA load ≥50 copies/mL) was compared through study week 48. Results. Patients either received an atazanavir-containing regimen (278 patients) or continued to receive a comparator PI-containing regimen (141 patients). The proportion of patients who experienced virologic rebound was significantly lower among those who switched to an atazanavir-containing regimen (19 7% of 278) than it was among those who continued to receive a comparator PI regimen (22 16% of 141; P = .004). Patients who switched to atazanavir therapy experienced significantly fewer total cholesterol, fasting triglyceride, and non—high density lipoprotein cholesterol elevations than did patients in the comparator PI group (P < .001); patients receiving atazanavir had comparable rates of adverse event—related discontinuation and serious adverse events. Conclusions. In patients with virologic suppression who were receiving other PIs, switching to a once-per-day regimen containing atazanavir provided better maintenance of virologic suppression (as demonstrated by significantly lower rates of virologic rebound and treatment failure than those observed with continued unmodified therapy), a comparable safety profile, and improved lipid parameters, compared with those for patients who continued their prior PI-based regimen through 48 weeks.