We evaluated the efficacy of a 5-drug salvage regimen, preceded by a 12-week, structured treatment interruption (STI), in 46 multidrug-treated, human immunodeficiency virus type 1-infected patients with detectable viremia. Patients were randomly assigned to receive a 5-drug salvage regimen immediately (noninterruption [NI] group; n = 24 patients) or after 12 weeks of STI (interruption [I] group; n = 22 patients). At week 48, 45% of patients in the I group and 46% of patients in the NI group had virus loads <50 HIV-1 RNA copies/mL (P = .619). No differences in CD4 cell counts were seen between groups at week 48 (P = .734). A complete reversion to wild-type genotype was detected in 35% of patients in the I group, but this phenomenon did not affect the virological response. The only overall baseline factor associated with ensuing virus suppression was a lower number of nucleoside reverse-transcriptase inhibitor-resistant mutations (relative risk, 0.66; 95% confidence interval, 0.47-0.93; P = .021). A prior STI seems to confer no additional benefit to subsequent virological or immunological outcomes of a salvage regimen.