Resistance to the action of endotoxin varies among inbred strains of mice, indicating that a component of this resistance has a genetic basis. Different responses to endotoxin that are characteristic of individual inbred strains represent phenotypes that can be used to genetically map the response modifier genes. This study compares the acute histologic lesions in 8-week-old male A/J and C57BL/6J (B6) mice injected intraperitoneally with endotoxin of E. coli O265:B6 (15 mg/kg). Animals of both strains exhibited splenitis, splenic lymphoid hyperplasia, splenic lymphoid necrosis, and sequestration of neutrophils in the pulmonary alveoli. The B6 mice showed increased margination of white blood cells to the pulmonary vascular endothelium relative to A/J mice. A large number of degenerating neutrophils was observed in the liver sinusoids of most B6 animals, while this lesion was much less severe in A/J mice. This difference was quantified, demonstrating a highly significant difference in neutrophil infiltration in B6 mice relative to A/J mice. Analysis of this phenotype in F1 mice demonstrates that major genes encoding the trait are not X-linked, imprinted, or maternally inherited and do not show the codominant inheritance expected if Lps(d) were primarily responsible. The distinctive, quantitative nature of these differences provides a useful assay for mapping genes that modify endotoxin responsiveness using the AXB and BXA recombinant inbred (RI) strains derived from A/J and B6 mice.