The pathogenesis of chronic hepatic allograft rejection is poorly understood. Recent studies suggested that hepatic mast cells may be involved in the pathogenesis of chronic cholestatic liver disease. Because chronic rejection after liver transplantation is predominantly a cholestatic process, the aim of this study is to determine whether hepatic mast cells are involved in its pathogenesis. Biopsy specimens from (1) normal livers (n = 5), (2) transplanted livers with end-stage chronic rejection (n = 8), and (3) transplanted livers with acute cellular rejection (mild, n = 7; moderate, n = 5; severe, n = 7) were studied. Biopsy specimens were stained immunohistochemically for mast cells with human antitryptase antibody. Mast cell density was significantly increased in the chronic-rejection group (4.9 +/- 0.6/mm2) compared with controls (2.9 +/- 0.5/mm2; P <.05). The percentage of portal tracts containing mast cells was significantly greater in chronic-rejection (89% +/- 8%) than control biopsy specimens (69% +/- 5%; P <.05), as was the average number of mast cells per portal tract (5.4 +/- 0.9 v 1.9 +/- 0.4 cells; P <.01). In chronic rejection, tissue mast cells frequently were seen surrounding damaged bile ducts in inflamed portal tracts. Neither mast cell density nor distribution was significantly different from controls in posttransplantation biopsy specimens with acute cellular rejection of mild, moderate, or severe degree. The finding of mast cells infiltrating portal tracts and surrounding damaged bile ducts in chronic rejection suggests that hepatic mast cells may be important effector cells in the pathogenesis of chronic rejection.