OBJECTIVES: Recent studies have shown that initiating treatment for major depressive disorders with venlafaxine may lead to lower subsequent treatment costs than the SSRIs and that three of the major SSRIs are similar to one another. Our objective is to provide updated evidence by comparing a year of depression-related costs for patients initiating therapy on any of three SSRIS with each other and with venlafaxine. METHODS: Patients with a depression diagnosis and a prescription for fluoxetine, paroxetine, sertraline, or venlafaxine between October 1997 and September 1998 were selected from Protocare Sciences' managed care claims database. After excluding patients who had antidepressant prescriptions within 6 months prior to their index prescription and patients with any antipsychotic prescriptions, 8800 remained for study. Logit propensity score models were constructed of the therapy initiation choices. The patients were stratified according to propensity score quintiles to reduce the potential therapy-selection bias. Within each stratum, the total claims costs, depression-related costs, and antidepressant prescription costs during the year following the patient's index antidepressant were computed and compared in terms of mean differences and geometric mean ratios of pairs of antidepressants. Precision-weighted ratios, confidence intervals, and overall significance levels were summed across all five strata. RESULTS: The precision-weighted geometric mean ratios of depression-related costs indicate that venlafaxine is higher than the SSRIs although with marginal significance (1.12,CI: 0.99-1.28), fluoxetine is higher than either paroxetine (1.33, CI: 1.23-1.43) or sertraline (1.31,CI: 1.22-1.40) and there is no significant difference between paroxetine and sertraline (0.99,CI: 0.93-1.05). However, the total costs of health care claims are not significantly different among the four study drugs. The mean (and median) depression-related costs are venlafaxine $1,324 ($540), fluoxetine $1139 ($558), paroxetine $1,022 ($391), and sertraline $925 ($425). CONCLUSIONS: In this managed care setting there is a difference in depression-related treatment costs between venlafaxine and the SSRIs and between fluoxetine and the other SSRIs, although the magnitude of the difference is not large.