Objective: To evaluate prospectively interferon alpha (IFN-α) associated effects on cerebral glucose metabolism and its correlation to neuropsychiatric symptoms during low-dose IFN-α-treatment. Methods: Eleven patients treated with low-dose IFN-α for chronic hepatitis C were prospectively evaluated by neuropsychiatric tests and cerebral [¹⁸F]deoxyglucose positron emission tomography (FDG-PET) before and in the 12th week of treatment. PET images were spatially normalized, corrected for variance in global activity and pixel-based t-statistics were calculated for each set of PET scans using SPM96 software. Pixel-cluster with P<0.001 for hypo- or hypermetabolism were displayed in parametric images. Covariance analysis with neuropsychiatric tests was calculated for each cluster. Results: In week 12 of IFN-α treatment, significant hypometabolism with a decrease of local activity ranging from 8 to 12% was found in all patients bilaterally in the prefrontal cortex (BA 9), which correlated in a covariate analysis with changes in depression score as measured by Beck's Depression Inventory. Additionally, hypermetabolism with a maximum increase in local activity of 6–8% was seen in all patients in putamina as well as the left occipital region (BA 18). Before IFN-α treatment, only 1/11 patient showed depressive symptomatology. After 3 months of treatment, 6/11 patients were classified as having mild to moderate depressive symptoms (P<0.1; Wilcoxon test). Conclusions: Low-dose IFN-α therapy is associated with significant prefrontal hypometabolism. This hypometabolism covaried with depression score, but was even found in clinically non-depressed patients. These findings may reflect a possible predisposing factor for IFN-α associated neuropsychiatric syndromes and might contribute to a pathophysiological model of affective disorders, as endogenous IFN-α levels are elevated in a subset of psychotic patients during acute disease.