Many physicians and patients wish to switch from successful protease inhibitor (PI)-based regimens to alternative regimens, usually composed of a nonnucleoside reverse transcriptase inhibitor (NNRTI) or abacavir plus two nucleoside reverse transcriptase inhibitors (NRTIs). This reflects a desire to avoid or reverse the metabolic changes observed during long-term PI-based antiretroviral therapy; to alleviate PI-associated adverse effects; and to improve adherence by simplifying the regimen. Data from a number of randomized and cohort PI switch studies are reviewed. Overall, the results of these studies are mixed, perhaps because of limitations in study design, patient number and duration of follow-up. In most studies, the frequency of virological failure is reduced by switching to a NNRTI regimen. Switching to an abacavir-based regimen is associated with two-fold higher risk of virological failure if mutations in the reverse transcriptase gene pre-exist. Improvements in metabolic and lipid abnormalities have not been uniform but favourable lipid changes have been reported, particularly after switching to nevirapine. Resolution of lipodystrophy symptoms has not been demonstrated objectively, perhaps because of insufficient follow-up and/or the role of NRTIs in this syndrome.