Objective: To evaluate the role of the eosinophil granulocyte during hepatic allograft rejection. Design: (a) A retrospective case-control study and (b) a prospective study of consecutive liver transplant recipients. Patients: In the retrospective study, eight patients with severe rejection in the first month after liver transplantation were compared with six patients without rejection. In the prospective study, 20 consecutive patients were studied for the presence of liver allograft rejection between March 1989 and October 1989. Measurements: Absolute eosinophil counts were determined whenever blood was drawn. Serum was analyzed for the presence of two eosinophil granule proteins, major basic protein and eosinophil-derived neurotoxin, on days 7, 14 and 21 after transplantation. Liver biopsy specimens were stained for the presence of major basic protein by means of immunofluorescence using a double-antibody staining technique. The degree of eosinophil infiltration and degranulation was graded using a panel of representative slides. Results: Blood eosinophilia was increased in patients with hepatic allograft rejection (p < 0.05). Serum major basic protein and eosinophil-derived neurotoxin concentrations were similar in patients with and without rejection. Many portal tracts of patients with rejection contained an abundance of eosinophils, and staining for major basic protein revealed the presence of intact eosinophils. In addition, extracellular major basic protein was seen, sometimes in the absence of intact eosinophils or an extensive infiltrate. In patients with severe allograft rejection, major basic protein staining was present in littoral cells lining the sinusoids. Conclusions: Patients with severe rejection in the first month after liver transplantation often have blood eosinophilia and marked infiltration of portal tracts with eosinophils or evidence of eosinophil degranulation. The presence of major basic protein likely is direct evidence of tissue destruction and may indicate active rejection (major basic protein in eosinophils and extracellular major basic protein, presence of portal infiltrate) or the immediate postinflammatory rejection state (extracellular major basic protein and major basic protein inside littoral cells, absence of portal infiltrate and eosinophils, bile ducts damaged or vanished). These findings underline the importance of the eosinophil as an intergral part of the rejection process. We conclude that the presence of eosinophils or their secretion products in the first month after liver transplantation is an indicator of ongoing or recent allograft rejection. (HEPATOLOGY 1994;20:654–662).