OBJECTIVES This study examined the effects of step therapy for antidepressants on prescription drug utilization and spending and other medical care utilization and spending. METHODS Study population employers who had implemented step therapy were compared to employers without step therapy using a pre/post design. Data were from the 2003 through 2006 MarketScan Research database, and the study sample consisted of employees and dependents who used antidepressants (n=15,552 patients whose employer implemented a step therapy protocol; and n=45,244 patients in the comparison group without step therapy). Multivariate generalized estimating equation models were used to estimate the effects of step therapy on medical and prescription drug spending and utilization while controlling for important covariates and adjusting for clustering by patient. RESULTS The effects of step therapy on the number of antidepressant days supplied per antidepressant user was characterized by an immediate drop in the number of antidepressant days supplied after implementation (coefficient -0.061, p<0.001). However, the number of antidepressant days supplied grew with time (coefficient 0.014 per quarter, p<0.001), and, 5 quarters after implementation of step therapy, the number of antidepressant days supplied in step therapy plans began to exceed the days supplied in comparison plans (i.e., in the fifth quarter after implementation the combined effect is -0.061 + 5*0.014 = 0.009). For antidepressant users, step therapy was associated with an increase in outpatient office visits and inpatient admissions and the increase remained relatively constant each quarter after step therapy began. Step therapy was also positively associated with the number of emergency room visits and the increase in emergency room visits grew with the amount of time elapsed since step therapy was implemented. CONCLUSIONS Rather than just shifting patients to lower cost antidepressants, step therapy may have the unintended effect of reducing overall antidepressant use and increasing medical care use and costs.