OBJECTIVE: To compare the depression-related health care expenditures among patients receiving mirtazapine, venlafaxine XR and sertraline in a managed care setting. METHODS: Pharmacy and medical claims were obtained for patients in three major health plans, for three months prior to and six months after their initiation of antidepressant therapy. Patients included in the study were 18 years or older; had a primary diagnosis of depression; had no depression-related costs in the pre-index period; had at least two prescriptions for the study antidepressant in the post-index period; were continuously eligible during the study period; and had no claims for substance abuse, schizophrenia or bipolar disorder. Cost comparisons were estimated using multivariate regressions after controlling for demographic and plan characteristics. RESULTS: Median depression-related costs after index date for patients prescribed mirtazapine (n=182), venlafaxine XR (n=469) and sertraline (n=4617) were $344, $374, and $326, respectively. Treatment with venlafaxine XR was associated with 11% higher (p=0.025) total costs compared to treatment with mirtazapine. There was no statistically significant difference in total depression-related costs between mirtazapine and sertraline (p=0.072). Similar results were obtained when pharmacy costs were used as a dependent variable in the multivariate model. CONCLUSIONS: Compared to sertraline and mirtazapine, venlafaxine XR was associated with significantly higher depression-related total costs. Treatment with mirtazapine was associated with higher depression-related total costs, but the results were not statistically significant.