We evaluated the expression of factor VIII and class II histocompatibility antigens on frozen sections of normal human and rat pancreases. The immunohistologic studies were performed with directly fluoresceinated anti-human factor VIII and monoclonal antibodies A2B5, 3G5 (anti-islet), L-243, I-2, OK1 (anti-human Ia-DR), Leu-10 (anti-human HLA-DQ), anti-human HLA-DP, and OX6 (anti-rat Ia). Islet endothelial cells of humans and Wistar, CD, and BB diabetes-prone rats could be distinguished from intra-acinar endothelial cells by markedly enhanced factor VIII immunoreactivity. Factor VIII-antibody staining of islet endothelial cells was specifically absorbed by prior incubation of anti-human factor VIII antibody with normal human plasma but not by incubation with factor VIII-deficient plasma. By double indirect immunofluorescence, normal human pancreatic ductal epithelium expressed Ia in five of six pancreases studied.