The success of well-developed protocols has been limited in real-world practice, where even effective strategies have not been sufficient to meet patient needs in routine clinical care owing to Axis I and III comorbidities. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial required that antidepressant medication treatment be optimal regarding dose and duration, yet accommodate flexibility to ensure safety given the wide range of comorbid general medical and psychiatric disorders allowed in the trial. The objective of this study was to develop a measurement-based care (MBC) approach and an automated feedback system to ensure adequate and safe antidepressant treatment delivery suitable for both clinical research and routine practice. Ratings of depressive symptom severity and side-effect frequency, intensity, and burden were obtained at each treatment visit using the MBC system that (1) guided medication dose adjustments and treatment duration, (2) documented clinician adherence to treatment recommendations, and (3) provided prompt feedback to clinicians to enhance appropriate treatment decisions. Physician adherence to protocol-specific treatment was monitored based on measured symptoms and side-effect burden, and dose and duration of antidepressant at each critical decision point during the acute phase treatment of major depression. Feedback was provided at the point of care by the clinical coordinators, assisted by Web-based reports following each treatment visit. On the basis of the first treatment step with citalopram, over 85% of treatment encounters had appropriate fidelity to recommendations. Most deviations from treatment recommendations occurred late in treatment and were often justifiable. MBC proved to be feasible and effective in busy primary and psychiatric settings. This approach signals a paradigm shift toward the use of measurement-based clinical decisions, both at the point of care and following each visit, to deliver optimal pharmacotherapy for depression.