C4d is a marker of the activated complement cascade used to assess the humoral component of rejection, mostly in kidney allograft transplants. The role of C4d deposition has recently been addressed in hepatic allograft but has never been tested in a series of inflammatory liver diseases without previous liver transplantation. The aim of this study was to compare the immunohistochemistry profile of C4d deposition in a pediatric population, between a cohort of patients with autoimmune hepatitis (AIH) and a series of patients with chronic viral hepatitis B or C. Immunohistochemical analysis was performed on 64 liver biopsies. C4d deposition was observed in 25 (83%) of 30 AIH biopsies examined, in 6 (40%) of 15 hepatitis C biopsies, and in 17 (89%) of 19 hepatitis B biopsies. No expression of C4d was observed in 4 noninflammatory liver specimens used as negative controls. In the AIH group, a staining of the periportal sinusoids was often observed, as well as focal periductal reinforcement. Centrolobular vein staining was observed in the 3 hepatitis groups with a higher frequency in viral hepatitis B biopsies. Regardless of the etiology, lymphoid aggregates demonstrated an accentuation of the staining. These results confirm a role for a humoral immune response in pediatric autoimmune as well as in viral hepatitis. The relative ratios of positive cases imply that this immunostaining does not represent a strong diagnostic criterion in the differentiation between viral hepatitis and AIH. However, differences in the pattern of the staining were observed, depending on the etiology of the disease. The high prevalence of C4d reactivity in viral hepatitis strongly suggests that C4d does not represent a useful marker in the differentiation between acute rejection and viral hepatitis relapse in liver transplants.