Tissue perfusion was determined by cardiac index (Cl) and skeletal muscle capillary blood flow (MBF), and arteriovenous oxygen difference (AVD) and oxygen uptake were compared in seven patients with severe spesis and eight nonseptic patients. Skeletal capillary muscle blood flow also was measured before and after a 2 day fast in 14 normal volunteers. In both septic and nonseptic patients, MBF varied directly with Cl. The average muscle blood flow was greater in septic than in nonseptic patients and, in addition, was greater per unit Cl. AVD in septic patients was narrower than in nonseptic patients. Septic patients with an AVD of less than 4 ml. of O2 had markedly higher MBF and Cl than did septic patients with an AVD greater than 4 ml. of O2. Fasting normal volunteers who, like the septic patients, would be catabolic had a significant increase in MBF during the fast. Although peripheral shunts are not ruled out ans an explanation of the hyperdynamic circulation in sepsis, the evidence is against their existence, at least in skeletal muscle, since capillary flow increases in direct proportion to cardiac output. If capillary flow is increased in fact in sepsis, then flow like blood pressure becomes less of a critical factor in explaining the demise of the septic patient. It might be postulated that the increased capillary flow seen in sepsis is secondary to the mobilization of amino acids from the body cell mass for gluconeogenesis and energy.