To induce graft-versus-host reaction (GVHR), C57B1/6 (B6) spleen cells were injected into (B6 x bm1)F1, (B6 x bm12)F1, and (bm1 x bm12)F1 mice. Since the strains bm1 and bm12 are mutant at the H-2Kb and I-Ab regions of major histocompatibility complex (MHC), respectively, we can assess MHC class I- or class II-different GVHR. As reported earlier, immunological perturbations assessed by the number of immunoglobulin-producing cells and immune complex deposition in renal glomeruli were demonstrated in MHC class II-different GVHR. A conspicuous finding in this report is that epithelioid granuloma formation was observed in the portal area and around the central vein of liver of (B6 x bm12)F1 mice injected with B6 spleen cells. The epithelioid granuloma formation was not observed in (B6 x bm1)F1 nor (bm1 x bm12)F1 recipient mice. Degenerative changes resembling chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis were also observed in the bile duct epithelium in (B6 x bm12)F1 and (bm1 x bm12)F1 mice. These lesions were already obvious at the 2 week postinjection of donor cells and were continuously observed up to 10 weeks when immunological perturbations subsided. Thus, class II-disparate GVHR in this experimental system might provide a novel animal model of protracted disease, primary biliary cirrhosis.