The expression of MHC class I and class II antigens was investigated in a model of acute pancreas allograft rejection in the rat. Pancreaticoduodenal and duct-ligated DA(RT1a)-to-LEW(RT1(1] and LEW(RT1(1]-to-LEW.1U(RT1u) pancreas grafts were compared with normal organs and with LEW(RT1(1] isografts at daily intervals from day 1 to day 10 after transplantation. The results show profound changes of MHC antigen distribution in allografts during the process of rejection. Exocrine acinar cells, being class-I-antigen-negative in the normal pancreas, strongly express these antigens during rejection. Class II antigens, normally not found in pancreatic endothelia or parenchymal cells, appear in duct epithelia, acinar cells, and endothelia of big vessels. Endocrine islet cells and smooth muscle cells stay Ia-negative throughout the rejection process. Focal class I reactivity is also observed in acinar cells of pancreaticoduodenal isografts; but class II antigens are neither seen in parenchymal cells nor in endothelia of any isograft. Thus, in the rat pancreas allograft model, the induction of class II antigens is an early phenomenon characteristic of an ongoing immune response, and it provides a valuable new diagnostic criterion. Antibodies reactive exclusively with donor-haplotype antigens demonstrate an increase in donor-derived class I and class II antigen-positive interstitial cells in addition to parenchymal antigenic changes. A possible effect of the antigenic alteration described on the course of the rejection process is discussed.