Treatment of human immunodeficiency virus type 1 (HIV-1) infection with regimens that include protease inhibitors (PIs) has contributed to marked improvements in HIV-related disease progression and mortality. Five PIs are approved by the US Food and Drug Administration and have potent activity in vitro. PIs with 2 nucleoside analogue reverse transcriptase inhibitors have demonstrated prolonged suppression of HIV-1 replication in treated patients and improvements in disease progression and mortality. PIs combined with nonnucleoside reverse transcriptase inhibitors or other PIs produce marked antiretroviral effects. Although not all patients have prolonged responses to PIs, and salvage treatment has had mixed results for patients who have not responded to initial PI therapy or whose HIV RNA levels have relapsed during such therapy, newer PIs currently being developed hold promise. Most patients can successfully tolerate PI-including regimens; however, long-term side effects, such as body fat redistribution, insulin resistance, and increased serum lipids, are now being observed in some patients receiving PI-including therapy.