In this paper we show that in viral hepatitis most Kupffer cells (KCs) are activated and express high levels of CD80, CD40, and class-II MHC molecules, thus acquiring the phenotype of professional antigen presenting cells (APCs). Activated KCs display a close contact with CD4ุ T lymphocytes and form KCs-T lymphocyte clusters. Clusters are found within the sinusoids, across the sinusoid wall, and within the liver parenchima as well, as a consequence of transendothelial migration (TEM). The positivity of activated KCs for hepatitis C virus (HCV) antigens, which likely reflects phagocytosis of infected hepatocytes, suggests that KCs-T cell clusters represent the morphological expression of the functional interaction between KCs acting as professional APCs and antigen-experienced CD4ุ T lymphocytes within the liver. These phenotypic and morphological changes are distinct features of livers in chronic hepatitis patients compared with controls. (HEPATOLOGY 1998;27:1600-1606.) Kupffer cells (KCs) are part of the body-wide distributed monocyte/macrophage system and are normaly found in the liver sinusoids, in close contact with the endothelial cells. 1 The anatomical localization of KCs within the liver sinusoids in the context of a low blood pressure vascular bed favours a direct contact with blood recirculating cells. KCs, as scavenger macrophages, are actively phagocytic and respond to bacteria and their products by releasing inflammatory cytokines, such as interleukin 1 and tumor necrosis factor alfa, 2 and by upregulating surface adhesion and co-signaling molecules. 3 Thus, activated KCs play a pivotal role in starting the acute phase response. 4 In this study we investigated the immunophenotype of KCs in situ, in chronic hepatitis of viral etiology compared with that of uninfected livers. We show that most KCs undergo activation in livers infected by HCV 5,6 and express surface molecules, such as CD80, CD40, and MHC-II, which are usually involved in the interaction between T and accessory cells. 7 Moreover, activated KCs phagocyte HCV-infected hepatocytes and form ''clusters'' with CD4ฯฉ T lymphocytes. These observations are consistent with the notion that KC-T cell clusters may represent the morphological expression of reciprocal KC-T cell activation.