Inoculation of eight chimpanzees with factor VIII, factor IX, or "H" strain plasma resulted in enzymatic and histopathologic evidence of non-A/non-B hepatitis in all eight animals. Challenge of two chimpanzees convalescent from factor VIII-induced disease with either factor IX or "H" strain plasma resulted in non-A/non-B hepatitis only in the animal inoculated with factor IX materials. Reciprocal cross-challenge of a chimpanzee convalescent from factor IX-induced disease with factor VIII also produced unequivocal enzymatic and histopathologic evidence of non-A/non-B hepatitis. Cross-challenge of a chimpanzee convalescent from "H" strain-induced non-A/non-B hepatitis with factor VII did not cause a second bout of non-A/non-B hepatitis. These findings suggest the factor VIII materials and "H" strain plasma used in these studies share a common etiologic agent (or agents), but that factor VIII and factor IX may contain two distinct agents. Electron microscopic (EM) examination of thin-sectioned, acute-phase liver biopsies from all but one of the chimpanzees receiving the primary inocula revealed the presence of abnormal hepatocyte cytoplasmic structures previously shown to be associated with non-A/non-B hepatitis. Crystalline structure containing 25 to 30 nm particles were visualized by EM in the cytoplasm of endothelial or Kupffer cells in acute-phase liver biopsies obtained from three chimpanzees inoculated with either factor VIII materials or "H" strain plasma.