Prior research demonstrates that improved medication adherence can produce substantial total health care savings. However, limited evidence exists to support the value of interventions to improve medication adherence. This article describes a method using alerts mailed to prescribers to improve adherence to antidepressants. The primary aim of the study evaluated the impact of written, patient-specific medication adherence alerts mailed to prescribers on overall depression-related health care costs associated with the use of antidepressant medications. The study used a clinical alert system that integrates medical and pharmacy claims data to identify and notify prescribers about patient-specific care gaps in the outpatient setting. This retrospective and observational study used health care claims from a high-risk population to match patients, identify conditions, and identify early discontinuation of antidepressant medications. The claims also allowed us to calculate changes in overall health care costs related to depression. The results show that mailing an alert to the prescriber increases the number of patients that have prescriptions for antidepressants six months after an alert from approximately 8% to 35%. The analysis further indicated that when a patient restarts their antidepressant and continues for at least six months, their follow-up medical plus pharmacy costs will be approximate $2,671 less than if they remain non-compliant. The study supports the use of a computer system to integrate health care claims data, identify care gaps, and generate written alerts to be mailed to prescribers as a means to improve patient adherence and lower total health care costs in patients receiving antidepressants.