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In this pilot study, we compared the economic impact of paroxetine and imipramine treatment of depressed outpatients from a university teaching hospital and a community mental health center. A 12-month retrospective chart review of patients was performed. Clinical outcomes including clinic usage, death, relapse, function, adverse effects, psychiatrist visits, and drug costs were evaluated. We analyzed drug costs, psychiatrist costs, and total direct costs using the Mann-Whitney U Test. The incidence of clinic usage, death, function, adverse effects, and psychiatrist visits was similar in patients treated with paroxetine (n = 12) and imipramine (n = 13). Two patients in the imipramine group were hospitalized once for a total of 5 days compared with none in the paroxetine group. Paroxetine drug costs were significantly higher than imipramine drug costs. Direct total costs (i.e., drug, psychiatrist visits, blood levels, and hospitalization costs) did not differ significantly between the groups based on actual drug usage (paroxetine: median $1,432.50 per patient per year; imipramine: median $1,425.81 per patient per year). Although the median direct total cost per patient per year for patients who received 12 months of therapy was lower in the paroxetine group ($1,479.90, n = 8) than the imipramine group ($1,503.61, n = 8), the difference was not significant. Our cost minimization analysis revealed no significant difference in the total cost between the two groups. However, the major cost in the paroxetine group was drug cost, whereas the major cost in the imipramine group was hospitalizations. Future large prospective trials are needed to validate these findings.