Objective: To examine the impact of duloxetine, venlafaxine and escitalopram use and associated copays on medication persistence, HEDIS standards for depression, medical utilization and health care costs. Methods: Medical and pharmacy claims data were used to develop a sample of adult users with: a) minimum two claims for duloxetine, escitalopram or venlafaxine XR; b) maximum 120 days between the index (initial)and last claim for a target drug; and c) minimum of 6 months enrollment following the index claim. Propensity analysis was used to match individuals in each drug group based on age, gender, risk adjuster, and disease severity. Multiple regression was used to examine the impact of anti-depressant use and prescription copays on the change in days supply (persistence), likelihood of meeting HEDIS standards, total pharmacy and medical expenditures, and medical utilization. Results: Over a 6-month period, a $10 increase in prescription copay resulted in a one day decrease in persistence for duloxetine users and a half day increase in persistence for venlafaxine users compared to escitalopram users. Increase in prescription copay was associated with greater likelihood of meeting HEDIS standards for all drug therapy groups. Venlafaxine users were 1.06 times more likely to meet HEDIS standards than escitalopram users. A $10 increase in prescription copay increased pharmacy costs by $12 per member for duloxetine users and $15 per member for venlafaxine users compared to escitalopram users. A $10 increase in prescription copay decreased total health care costs by $4.30 per member. Increased prescription copay resulted in non-significant reductions in the utilization of inpatient admissions, ER and outpatient visits. Conclusion: Higher prescription copays reduced persistence and pharmacy expenditures for antidepressant users. Smaller decreases in health care expenditures were also seen. Health plan decision makers should consider the impact of prescription copays on patient behavior and all components of health care expenditures.