Cellular changes in the liver were studied during an acute lethal graft‐versus‐host (GVH) disease in relation to the expression of major histocompatibility complex (MHC) antigens on different liver cells‐ Screening for MHC antigen expression revealed that control livers contained very few Ia+ cells: mainly cells in the portal tract interstitium and and a small percentage of the Kupffer cells. The changes during an ongoing GVH reaction could he separated into those related to the sinusoid‐associated cells, including the liver parenchyma, and those related to the portal‐tract‐associated cells, including periportal hepalocytes In the sinusoids an increase in the number of Kupffer cells was seen, mm all expressing Ia+antigens No damage to hepatocytes or other sinusoid‐associated cells was observed 1l is postulated that the increase in both number and Ia+expression of the Kupffer cells is most probably due to an increased phagocytic uptake of Mood‐borne cellular debris and is not a result of extensive damage to hepatocytes. In the portal tracts expanding infiltrates were found composed of Ia+T ceils and macrophages (ratio 2:1). These infiltrates are probably due to a local accumulation of lymphocytes and macrophages as a result of an interaction of migrating donor‐type alloreactive T cells with recipient type Ia+cells present in the portal tract interstitium. which also interfered with normal recipient lymphocyte and macrophage traffic. Damage to portal‐tract‐associated cells was slight and confined to bile duct epithelial cells, which now expressed Ia+antigens, and to periportal hepatocytes. In conclusion, these data do not indicate that damage to liver parenchyma plays a major role in the pathogenesis of