To compare skeletal muscle microvascular blood flow at rest and during reactive hyperemia in septic patients, a prospective, controlled trial was conducted on 16 patients with severe sepsis and a control group of 10 patients free of infection in the intensive care unit of a university hospital. Systemic hemodynamics, whole-body oxygen transport, and skeletal muscle microvascular blood flow at rest and during reactive hyperemia were measured. Reactive hyperemia was produced by arrest of leg blood flow with a pneumatic cuff; on completion of the 3 min ischemic phase the occluding cuff was rapidly deflated to 0. Hemodynamic and oxygen-derived variables were determined invasively. Skeletal muscle microvascular blood flow data were obtained using a laser Doppler flowmetry technique and values expressed in millivolts. Whole-body oxygen delivery in septic patients was increased compared with control subjects. Resting skeletal muscle blood flow was decreased in septic patients compared with control subjects (233 +/- 52 versus 394 +/- 93 mV; p < 0.05). Peak flow during reactive hyperemia was also decreased in septic patients compared with control subjects (380 +/- 13 versus 2,033 +/- 853 mV; p < 0.05). Cyclic variation in blood flow (vasomotion) was observed in control subjects but not in septic patients. Skeletal muscle microvascular perfusion is altered in patients with severe sepsis despite normal or elevated whole-body oxygen delivery. These microvascular abnormalities may further compromise tissue nutrient flow and may contribute to the development of organ failure in septic patients.