IFN alpha treatment is able to produce dose-related side effects, such as depression, in the central nervous system. We assessed the effects on depression of four different types of IFN alpha (recombinant IFN alpha 2a, recombinant IFN alpha 2b, lymphoblastoid IFN alpha, leukocyte IFN alpha), administered at the same doses in four homogeneous groups of chronic hepatitis C patients (96 patients; 24 patients for each group). A group of 18 untreated hepatitis C patients was considered as a control group. Depression was measured using Zung's self-rating depression scale (SDS scale) before starting IFN alpha therapy and at the 1st, 3rd and 6th month of treatment. In all patients evaluated, mean SDS values increased from mild to moderate depression, but never attained severe depression (SDS > 70). More elevated SDS values were observed in the 1st month of treatment, with a progressive decrease during the end points above-mentioned. The recombinant IFN alpha 2a and lymphoblastoid IFN alpha arms presented higher SDS mean scores compared to the recombinant IFN alpha 2b and leukocyte IFN alpha arm. Only in the leukocyte IFN alpha arm SDS values returned to basal values at the 6-month end point. Leukocyte IFN alpha seemed to present a more elevated tolerability than other IFN alpha types available for clinical practice. A very careful selection of hepatitis C patients is required before starting IFN alpha therapy.