Background: Optimal adherence to highly active antiretroviral therapy (HAART) is necessary to achieve the best and the most durable benefit. Many factors may influence compliance to such demanding regimens, and their identification may help in the design of strategies to enhance adherence. Purpose: To assess the factors associated with lower compliance to therapy, the causes of nonadherence, and the relation of nonadherence with virologic response. Method: We performed an observational, cross-sectional study on HIV-infected patients (pts) receiving unrestricted HAART and attending our clinic from January to May 2001. Pts completed a self-administered (ACTG modified) questionnaire on adherence to their therapy. Virologic response was defined as undetectable viral load at the time of interview. A regression model was used to determine predictors of adherence. Results: 597 out of 623 pts (95.8%) completed the survey. Mean age was 38.2 years (range, 18-79). A total of 448 pts (75.0%) were men, 323 (54.1%) were intravenous drug users, 196 (32.8%) were heterosexuals, 76 (12.7%) were men who have sex with men. Mean time on therapy was 49.3 months (range, 4-145). All pts were on stable therapy (>4 months), 173 pts (29%) were on their first HAART regimen, 309 pts (51.7%) were on NNRTI-based regimen, and 288 pts (48.2%) were on a PI-containing treatment. A total of 304 pts (50.9%) were categorized as adherent (p = .024). Multiple logistic regression showed that older age (p = .002), lower number of pills (p = .024), fewer daily doses (p = .002), and shorter time on therapy (p < .001) were factors associated with adherent behavior. Forgetfulness (59.3%), being away from home (50.2%), and problems with schedule (37.6%) were the most frequent causes of nonadherence. Adherent pts were more likely to have undetectable viral load than nonadherent pts (76.5% vs. 55.3%; p < .0001). Conclusion: Younger age, higher number of pills, higher frequency of doses, and longer time on therapy were predictors of nonadherent behavior. Optimal adherence correlated with the best virologic response. Simpler regimens with a lower number of pills and doses may help patients' compliance to therapy.