The aim of this study was to confirm that microvascular perfusion was abnormal during the early phases of normotensive sepsis and to determine whether these changes were due to the development of tissue edema. Skeletal muscle red blood cell (RBC) flow was studied in rats made septic by cecal ligation and perforation (CLP). After anesthesia with halothane, arterial and venous cannulae were inserted and, in the treatment group, a CLP performed. At 6, 24, and 48 h after entry into the study, the incidence of microcirculatory absence of flow in the extensor digitorum longus muscle (EDL) was examined with intravital microscopy. The number of capillaries containing RBCs were counted over a 60-s interval, and the flow status of each capillary was recorded. A significant increase in the number of stopped-flow capillaries was observed in the CLP group (p < 0.01) as compared with time-matched controls. In both groups the number of capillaries with stopped flow was greater than in naive animals. The severity of absence of flow was negatively correlated with the systemic hemoglobin concentration. These changes were not associated with an increase in tissue wet/dry weight ratio or albumin flux. This study shows that sepsis was associated with increased RBC flow heterogeneity. These changes, which occur within 24 h of the septic insult, are a persistent feature of the evolving septic process in the absence of tissue edema. These observations support the view that extrinsic compression of the microcirculation by tissue edema is not the primary cause of alterations in microcirculatory flow in sepsis.