AimPsychiatric side-effects are the main reason for discontinuation of interferon (IFN)-based therapy. Recent developments in near-infrared spectroscopy (NIRS) have enabled non-invasive clarification of brain functions in psychiatric disorders. We prospectively evaluated brain activation in 20 chronic hepatitis C patients with or without IFN-based therapy by using NIRS during a verbal fluency task (VFT). MethodsThe relative concentrations of oxygenated hemoglobin were measured while patients completed a questionnaire survey at the start of treatment and at 4 and 12weeks during treatment, using NIRS. ResultsThe VFT performance did not change among the two groups. Patients with IFN-based therapy showed significantly lower activation during VFT in frontal channels at 12weeks than those at the start of treatment and control (P<0.05). Their Center for Epidemiologic Studies Depression Scale scores were significantly higher at 12weeks than those at the start of treatment, although major depressive symptoms were not found (8.37.9 vs. 13.2 +/- 6.0, P<0.001). ConclusionThe decrease in oxygenated hemoglobin concentrations of the frontal lobe detected using NIRS in this study reflects hypofunction of the frontal lobe. This functional decline that was caused by IFN-based therapy may be associated with the prodromal phase of depression.