To evaluate the impact of telephone counseling and educational materials on medication adherence and persistency among members with newly diagnosed depression enrolled in a pharmacy benefit management-sponsored disease management program. Longitudinal cohort observation. The study population comprised 505 members with a new or recurrent episode of depression who consented and enrolled in a depression disease management program. After written consent was obtained, program participants received up to 4 telephone-counseling calls and 5 educational mailings focused on the importance of medication compliance, barriers to medication compliance, quality of life, symptoms, and satisfaction with the program. A control group of 3744 members was selected from client companies that opted not to offer the depression program. Measures of medication adherence, persistency with prescription drug therapy, and patient refill timeliness were computed for both groups and compared. Patients enrolled in the depression disease management program were significantly more likely to adhere to their medication regimen during acute (89.0% vs 67.7%, P < .001) and continuation treatment phases (81.1% vs 57.6%, P < .001). In addition, members enrolled in the program were significantly more likely to continue their therapy after 7 months (77.8% vs 49.5%, P < .001) and refilled their prescriptions on a more timely basis (0 vs 18 days, P < .001). A pharmacy benefit management-sponsored health management depression program succeeded in encouraging patients with new or recurrent depression to stay on antidepressant medication and to reach treatment goals outlined by best practice guidelines.