Many patients infected with human immunodeficiency virus type 1 (HIV-1) have suboptimal responses to protease inhibitor-based therapy. We retrospectively evaluated a cohort of 104 HIV-positive adults, most of whom had previously received antiretrovirals, to identify the frequency and clinical predictors of incomplete response to potent HIV-1 protease inhibitors. Sixty-two (60%) of the patients had an incomplete response, defined as a plasma HIV-1 RNA level of >400 copies/mL after 20 weeks of therapy. Logistic regression analysis identified the following independent risk factors for incomplete response: elevated baseline plasma HIV-1 RNA level (P = .03), low baseline weight (P = .01), chemoprophylaxis for Pneumocystis carinii pneumonia (P = .04), and active illicit drug use (P = .04). Regular prescription of narcotics or benzodiazepine anxiolytics (P = .01) and use of any Internet site (P = .01) predicted a more favorable response. Identifying factors that predict suboptimal response to protease inhibitors improves our understanding of interpatient variability in response to therapy and should foster strategies that enhance the effectiveness of current and future regimens.