OBJECTIVES: To evaluate whether nefazodone HCl s clinical attributes translate to depression-related economic savings during the first six months of antidepressant therapy, relative to bupropion, fluoxetine, paroxetine, sertraline, and venlafaxine. METHODS: We screened the pharmacy and medical claims for all members of a large, geographically diverse managed care organization who were prescribed an antidepressant for the diagnosis of a depressive disorder during the period 1/95 through 6/98. Patients had initiated new episodes of antidepressant therapy and were characterized by having no preexisting anxiolytic or sedative/hypnotic use. The six-month window immediately following antidepressant initiation was screened for two primary outcomes: depression-related pharmacy cost and depression-related medical cost (drawn from all medical services for which a diagnosis of depression was recorded). Depression-related pharmacy cost was defined as the cost incurred by the payor for the index antidepressant, as well as the costs for any additional medications, such as anxiolytics, sedative/hypnotics, and low-dose older antidepressants. RESULTS: A total of 1,961 antidepressant users satisfied our eligibility criteria. The rate of concomitant medication utilization among nefazodone users within six months of antidepressant initiation was nearly twofold lower (11.9%) than with the other antidepressant treatment groups (19.7%-27.9%). After adjusting for age, gender, and prior total 4-month medical and pharmacy utilization using a multivariate regression analysis, nefazodone emerged as a significant predictor of 6-month depression-related pharmacy and medical cost savings. Nefazodone was associated with a cost reduction of $129 per patient, relative to non-nefazodone treatment (p<.05). When compared with nefazodone, each antidepressant treatment group was associated with significant incremental 6-month depression-related cost (p<.05 for each comparison). CONCLUSIONS: Nefazodone s co-prescription rate was approximately one-half that observed for fluoxetine, paroxetine, sertraline, venlafaxine, and bupropion. It was a significant predictor of 6-month depression-related cost savings to the payer.