In this study, the authors attempted to determine predictors of adherence to antidepressant therapy and to identify specific educational messages, side effects, and features of doctor-patient collaboration that influence adherence. Patients newly prescribed antidepressants for depression at a health maintenance organization were identified by using automated pharmacy data and medical records review. Patients (n = 155) were interviewed 1 and 4 months after starting antidepressant medication. Approximately 28% of patients stopped taking antidepressants during the first month of therapy, and 44% had stopped taking them by the third month of therapy. Patients who received the following five specific educational messages--1) take the medication daily; 2) antidepressants must be taken for 2 to 4 weeks for a noticeable effect; 3) continue to take medicine even if feeling better; 4) do not stop taking antidepressant without checking with the physician; and 5) specific instructions regarding what to do to resolve questions regarding antidepressants--were more likely to comply during the first month of antidepressant therapy. Asking about prior experience with antidepressants and discussions about scheduling pleasant activities also were related to early adherence. Side effects, only at severe levels, were associated with early noncompliance. Neuroticism, depression severity, and other patient characteristics did not predict adherence. Primary care physicians may be able to enhance adherence to antidepressant therapy by simple and specific educational messages easily integrated into primary care visits.