OBJECTIVES: Clinically, interferon-alpha (IFN-α) is used for inhibiting hepatitis B and C virus infection, but IFN-α treatment may cause side effects of depression. Recent study has reported that serum serotonin levels are associated with antiviral therapy outcomes in patients with chronic hepatitis C. The aim of this study was to evaluate the cost and effectiveness of antidepressants in hepatitis C patients treated with interferon. METHODS: This is a retrospective study from January 1, 2002 to December 31, 2010 using Chi-Mei Medical Center claim data. Subjects were divided into exposure and control groups. The exposure group included patients treated with IFN-α or combined antiviral drugs and antidepressants for at least 6 months. The control group was those without antidepressant treatment. The endpoints were evaluated liver related lab data, the number of visits to the out-patient department, emergency department or admission during treatment, and the cost. RESULTS: There were a total of 135 patient diagnosed hepatitis B or C and treated with IFN-α or combined antiviral drugs. Comparing the exposure and control groups, the control group had a higher SGOT (53.97±40.0 vs. 93.16±64.54 IU/L, 95% CI=28.12~50.3, P<0.05); SGPT (62.07±5. IU/L vs. 316.36±123.4 IU/L, 95% CI=79.95~122.64, P<0.05), AFP (9.8±22.4 ng/mL vs. 11.79±18.1 ng/mL, 95% CI=-1.77~5.7, P=0.304). Comparing mean healthcare costs in six months is NT 263,200 for exposure group and 242,600 for control group. No significant difference. That may be related to psychiatric visits and medication use. CONCLUSIONS: These results suggest that antidepressants may play an important role in hepatitis B or C patients treated with IFN-α or combined antiviral drugs. Future studies are needed to further clarify the mechanisms of antidepressant action.