The prevalence of phenotypic drug resistance was assessed in 60 patients with a viral rebound after they received a protease inhibitor (PI)- or nonnucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen (baseline). Resistance testing was done within 36 weeks of viral rebound; no resistance testing was available at baseline. All patients had previously received zidovudine; 86.0% had received lamivudine. In total, 45.1% of the patients had strains resistant to the PI that they started and 88.9% given nevirapine had strains with reduced susceptibility to that drug. Overall, 46 patients (76.7%) harbored a strain resistant to >/=1 drug of their initial PI- or NNRTI-containing regimen. Of 53 patients who remained on treatment at the time of the study (40 had switched to a different combination from that at baseline), 6 harbored isolates susceptible to all drugs they had ever received. Thus, patients with viral rebound while on potent antiretroviral therapy usually have reduced susceptibility to >/=1 drug. Viral rebound also occurs in persons in whom resistant strains could not be detected by the assay used.