Changes in glucose uptake and lactate and alanine release by skeletal muscle were studied in anesthetized dogs before and over a 4-h period after endotoxin administration and in time-matched controls. Blood flow was measured directly, and arteriovenous differences of glucose, lactate, alanine, and O2 were determined in hindlimb muscles by obtaining blood samples simultaneously from the carotid artery and profunda femoris veins. Skeletal muscle blood flow decreased by 29% after endotoxin, reflecting a similar average decrease in cardiac output. Mean arterial glucose decreased 31% and arterial lactate and alanine increased 201 and 123%, respectively, after endotoxin administration. Skeletal muscle glucose uptake increased 57% after endotoxin despite the progressively developing hypoglycemia. Postendotoxin lactate and alanine release were also elevated by 217 and 82%, respectively. Average O2 consumption by skeletal muscle did not change. The metabolic pattern observed after endotoxin administration suggests that the increased lactate and alanine release are likely to be related to the elevated glucose uptake and that skeletal muscle greatly influences the metabolic pattern observed during shock.