In this article, health care expenditures are assessed for patients diagnosed with depression who are being treated with either venlafaxine (immediate or extended release) or a selective serotonin-reuptake inhibitor (SSRI). Patients beginning treatment for a new depressive episode were identified retrospectively from 1994 to 1998. Before beginning therapy, patients prescribed venlafaxine (N = 353) had more nonmental illnesses (0.84 vs. 0.75 clinical events/patient, respectively; P < .01) and hospitalizations for mental illness (0.56 vs. 0.30 hospitalizations/patient; P = .06) than patients prescribed SSRIs (N = 7,330). In the six months after initiating treatment, venlafaxine was associated with lower hospitalization expenditures for nonmental illness than were SSRIs ($206 vs. $472, respectively; P = .02), but total health care expenditures were not significantly different.