This study examines the role of neutrophils (PMN) in the pathogenesis of the endothelial lesion induced by a single sublethal dose of endotoxin. It is intended to clarify whether the margination of PMN on endothelium after endotoxin causes intimal injury or is a response to it. Neutropenic rabbits had mean PMN counts of 33/cu mm 72 hr after nitrogen mustard (HN2). They were heparinized and given either intravenous endotoxin or saline and were sacrificed 30-60 min later. Preterminal blood samples were positive for the presence of endothelium in 77% of endotoxin-treated neutropenic rabbits, in 87% of endotoxin-treated normal rabbits, and in only 12% of neutropenic rabbits given saline. Sections of aorta revealed marked abnormalities of endothelium in rabbits receiving endotoxin, whether neutropenic (90% had lesions) or normal (85% had lesions). Endothelial abnormalities included vacuolation and lysis, marked subendothelial edema, and desquamation. Similar lesions in control neutropenic rabbits were not found, and mild abnormalities were seen only rarely. These data indicate that neutropenia does not protect rabbits from endothelial injury due to endotoxin. They further suggest that HN2 may cause endothelial damage either directly or secondary to the effects of neutropenia.