Virologic relapse occurs within 1 to 2 years of antiretroviral therapy in up to 50 percent of HIV-infected individuals. The best treatment approach for patients who experience virologic rebound while on highly active antiretroviral therapy (HAART) has not been defined. Current guidelines recommend switching to a new treatment regimen shortly after virologic rebound in an effort to avoid sequential accumulation of multiple resistance mutations. However, early treatment switching has numerous disadvantages: risk of virologic rebound on the new therapy, a limited number of drug combinations available to treat such rebounds, and difficulty in obtaining early genotypic and phenotypic drug-resistance information to guide treatment modification. Delaying a switch to a new antiretroviral regimen has the advantage of preserving future treatment options, and HIV levels may remain partially suppressed even after drug-resistant mutants emerge. Moreover, several observational studies describe maintenance of immunologic and clinical benefits of HAART even after virologic rebound. Delayed treatment switches, however, raise concerns about sequential accumulation of drug resistance mutations that may diminish the chances of viral resuppression with successive HAART regimens, and the long-term immune consequences of virologic rebound on HAART are not known. It is therefore important to evaluate the viral and immunologic responses among patients randomized to either an early or delayed HAART switch.