This laboratory has documented a progressively developing hypoglycemia associated with systemic hypotension, hepatosplanchnic pathology, and death in endotoxin-shocked dogs. Recent data documented accelerated uptake of glucose in blood following endotoxin, with certain components of the buffy coat responsible for the increased uptake. The present study utilizing the awake dog assayed a possible protective role of leukocytes against the lethal effects of endotoxin. Animals were divided into paired groups: saline controls (Group I) and endotoxin experimentals (Group II). Group II animals were injected intravenously with sublethal doses of E. coli endotoxin on 2 successive days (Days 1 and 2), LD100 on the third day, and 2 X LD100 on Day 4. The control group received equal volumes of saline on Days 1, 2, and 3, but on Day 4 received a superlethal dose of endotoxin identical to the experimental group. The awake dog became febrile and exhibited initial leukopenia with subsequent marked leukocytosis in response to endotoxin. Lethal hypoglycemia was not seen in animals demonstrating initial leukocytosis (zero time) on the day of superlethal endotoxin challenge, while animals with initial normal leukocyte counts died with low glucose concentrations (mean, 40 mg%). Results suggest that an initial leukocytosis and sustained gluconeogenic function are important factors in survivability to endotoxin shock.