Seventy-three patients infected with human immunodeficiency virus type 1 (HIV-1) were enrolled in a prospective observational study to investigate the efficacy and tolerance of substituting a nonnucleoside reverse transcriptase inhibitor (NNRTI) for a protease inhibitor (PI) in patients whose plasma viral load (pVL) was controlled by a PI regimen. After a median follow-up of 52 weeks, 63 patients (86.3%) had undetectable pVLs. The incidence of virological breakthrough at 12 months of follow-up was 6.5% (95% confidence interval [CI], 1-20) among patients who had been antiretroviral naive before receiving HAART and 19.2% (95% CI, 6-34) among patients who had been treated with antiretroviral drugs before receiving the PI regimen (P=.10).