The effects of interferon-γ and interleukin-2 on liver regeneration after 70% hepatectomy in rats was studied immunohistologically, with special attention paid to major histocompatibility complex class II antigen expression. Liver regeneration 2 days after partial hepatectomy as assessed on the basis of bromodeoxyuridine labeling index revealed that regeneration was inhibited significantly in rats given a single dose of interleukin-2 or interferon-γ compared with rats that underwent only partial hepatectomy. Simultaneous administration of interleukin-2 and interferon-γ inhibited liver regeneration more markedly than administration of either drug. In rats subjected to partial hepatectomy, Kupffer cells around the portal vein expressed slightly more major histocompatibility complex class II antigen than did sham-operated controls. In the group given interferon-γ, major histocompatibility complex class II antigen expression was markedly increased. Major histocompatibility complex class II antigen expression was greatest in most Kupffer cells of rats given both interleukin-2 and interferon-γ. These results suggest that interferon-γ activates (proliferating) Kupffer cells, in turn leading to suppression of liver regeneration. These major histocompatibility complex class II antigen–positive Kupffer cells act as antigen-presenting cells and present hepatocyte as antigen, the so-called abnormal self, to helper and cytotoxic T cells. Both types of T cells, in turn, may suppress hepatocyte proliferation. The various cytokines induced by the activated Kupffer cells and helper T cells seem to form a network with interferon-γ to regulate liver regeneration. (HEPATOLOGY 1993;18:340–346).