Antidepressants do not differ significantly in their ability to treat depression. Excluding the tricyclic antidepressants (TCAs), these drugs also do not differ significantly in their incidence of adverse events. Therefore, the initial choice of antidepressant medication should be based, in part, on cost. The objective of this study was to evaluate the impact on utilization and costs of a generic steptherapy edit for antidepressant drugs excluding TCAs in a health maintenance organization (HMO) in an integrated health system (IHS). The pharmacy department of the 440,000-member HMO in an IHS collaborated with the Behavioral Health Clinical Program to design an intervention that required generic antidepressants as first-line pharmacotherapy. Under the GenericStart! Program, a brand-name antidepressant was covered only after trial with a generic antidepressant, excluding TCAs. A step-therapy edit was added to the pharmacy claims processing system on January 1, 2005. All new starts, defined as members with no claims history of antidepressant treatment within the preceding 6 months, were required to use a generic antidepressant. The member copayment was waived for the first prescription. All generic antidepressants were in tier 1 of the drug formulary, with an average copayment of $5 to $10. All brand-name antidepressants were in either tier 2 (preferred brand), with an average copayment of $20 to $25 or 25% coinsurance, or tier 3 (nonformulary brand), with an average copayment of $40 to $45 or 50% coinsurance. Pharmacy claims data from a national pharmacy benefit manager (PBM) without interventions for antidepressants in 2004 or 2005 were used for the comparison group. The generic antidepressant dispensing rate increased by 20 points (32.5% to 52.5%) in the intervention group but only 7.4 points (24.9% to 32.3%) in the comparison group in 2005 compared with 2004. The principal measure of antidepressant drug cost per day of therapy in the intervention group decreased by 11.7% (from $2.40 to $2.12) in 2005 compared with 2004 versus a 2.7% decrease (from $2.60 to $2.53) in the comparison group (P <0.001). Days of antidepressant drug therapy per member per month (PMPM) dropped by 1.5% (from 1.74 to 1.71) in the intervention group versus a decrease of 5.0% (from 1.37 to 1.30) in the comparison group in 2005 compared with 2004. The combination of change in drug cost and utilization resulted in a 13.0% decrease in antidepressant drug cost, from $4.16 PMPM in 2004 to $3.62 in 2005, compared with a 7.6% decrease (from $3.57 to $3.30 PMPM) in the comparison group. The 9.0% difference in drug cost per day represents drug cost savings of approximately $0.36 PMPM or $1,880,562 in 2005 dollars for this HMO of approximately 440,000 members. A step-therapy edit requiring HMO members to use a generic antidepressant, excluding tricyclics, prior to use of a brand-name antidepressant resulted in drug cost savings of 9.0% for the entire class of antidepressants, equal to $1,880,562 ($0.36 PMPM) in 2005 dollars in the first year of the intervention. A small (-1.5%) decrease in use of antidepressants occurred in the intervention group, which was less than the 5.0% decrease in utilization of antidepressants in the comparison group.