We investigated, in a prospective cohort follow-up study, whether substituting efavirenz (EFV) for protease inhibitors (PIs) could be safe in HIV-infected patients with optimal viral suppression achieved on PI-containing regimens. In patients with undetectable plasma viral load (pVL) <50 copies/ml who were naive to therapy with nonnucleoside reverse transcriptase inhibitors (NNRTIs), PIs were replaced by EFV whereas associated nucleoside analogs (NAs) were retained. 62 patients were enrolled. Median follow-up on EFV was 64 weeks (2-88 weeks). Side effects due to EFV occurred in 48 patients. Two patients experienced a high level viral rebound due to diminished compliance; 55 (88.7%) maintained a pVL <50 copies/ml; 3 showed one episode of viremia (52-89 copies/ml); 2 stopped EFV before any VL control. Mean CD4 cell count did not change significantly. One AIDS patient experienced a single cutaneous recurrence of Kaposi's sarcoma after 40 weeks on EFV. Replacing PI with EFV in patients with optimal pVL suppression appears to be safe both virologically and immunologically.