Three methods of adherence to antiretroviral therapy were evaluated for 149 patients infected with human immunodeficiency virus (HIV): plasma level of protease inhibitors (PIs), patient self-report, and routine biological parameters associated with the use of some antiretroviral drugs. Adherence to therapy was estimated from a score calculated from answers to a self-administered questionnaire and on the basis of measurement of relevant plasma and blood levels. Of the 149 patients, 112 had a virologic response, and 122 had adequate trough PI levels. Plasma PI levels and virologic outcome were significantly correlated (P<.0001). The adherence score was significantly correlated with virologic response (P<.001). Macrocytosis was significantly associated with virologic response in the patients treated with zidovudine or stavudine (P=.006). PI level was the higher significant predictor of virologic response (P=.0003). Self-reported adherence (P=.01) and macrocytosis (P=.05) were also independently associated with antiretroviral efficacy.