Interferon (IFN)-alpha is regarded as an efficient therapy for chronic hepatitis C, despite the fact that less than 50% of patients receiving IFN-alpha are known to show an initial biochemical response, and several adverse reactions related to this therapy are becoming a serious clinical problem. For a more efficient and safer treatment of IFN-alpha, several pretreatment factors to predict a favorable or unfavorable response to IFN-alpha therapy are now being evaluated, such as hepatitis C virus (HCV)-RNA levels in serum and the genotypes of HCV. Recently, the hepatic iron concentration has been reported to influence the outcome of IFN-alpha therapy for chronic viral hepatitis. In the present study, whether hemosiderin deposition in liver is a histologic predictor of response to IFN-alpha therapy was evaluated, as well as which anatomical location showing the hemosiderin deposition was more closely related to the response to this therapy. Two factors, high titer of HCV-RNA in serum and hemosiderin deposition in portal endothelial cells, were found to be predictable factors of poor response to IFN-alpha therapy, and these two factors were found to be related to each other. Results showed that the hemosiderin deposition in portal endothelial vessels is an easily evaluable histologic finding, and clinicians and histopathologists are encouraged to use this finding when selecting patients with chronic hepatitis C suitable for IFN-alpha therapy.