Despite the importance of medication adherence in the management of depression, adherence rates for antidepressant therapy are poor. Failure to adhere to pharmaceutical therapy leads to poor clinical outcomes and increased health care costs. OBJECTIVE: To evaluate the impact of an interventional program on antidepressant medication adherence. METHODS: This was a prospective interventional program with retrospective adherence study using 24-month pharmacy claims database. Medication adherence measures included length of therapy, median gap, persistence over time, and procession ratio were obtained prior to and at 18 months post implementation of interventions. Physician educational interventions included on-site provider education, review of The Agency for Healthcare Research and Quality (AHRQ) guidelines for major depression, newsletter, and case management. Patient interventions included case managers followed up with non-compliant patients by phone for oral counseling, newsletter, incentive programs, and reminder postcards. RESULTS: A total of 4021 patients were included in the study. Significant improvements were observed at post intervention for all adherence parameters. The average length of therapy at outcome measure was 165 days compared to 131 days at baseline. Persistence over time showed 72% of patients completed their acute phase therapy (84 days) compared to 60% at baseline (p<0.001) and 55% of patients continued their continuation therapy (180 days) compared to 46% at baseline (p<0.001). The procession ratio over time at 180 days was 0.8, an improvement of 24% from the baseline. CONCLUSIONS: Results of our analysis indicated significant improvements in antidepressant medication adherence. The improvements seen in the antidepressant medication adherence improvement initiatives can be attributed to the strength of the interventional program. Although results of our study are encouraging, expanded effort is needed to further improve the persistence rate at 180 days.