This prospective, randomized, controlled experimental study looks at the effects on global and regional microvascular blood flow (RMBF) in an ovine model of septic shock after severe smoke inhalation injury. Sixteen sheep were randomized into two groups, a control group (no injury, n = 8) and a smoke/sepsis (SS) group (n = 8), which received an insufflation of 4 sets of 12 breaths of cotton smoke (<40°C) followed by instillation of live Pseudomonas aeruginosa into both lung lobes, according to an established protocol. All sheep were mechanically ventilated with 100% oxygen, and fluid resuscitated with lactated Ringer's solution for the entire duration of the 24-h experimental period to maintain hematocrit at baseline (BL) levels. Healthy control animals were not subjected to the injury and received only 4 × 12 breaths of room air and instillation of the vehicle (normal saline). Blood flow was analyzed using colored microspheres. Control animals remained hemodynamically stable and had no statistical changes from BL in visceral or cerebral blood flow during the entire experimental period. All SS animals developed a hypotensive, hyperdynamic circulation, characterized by a significant increase in heart rate and cardiac output with a simultaneous significant fall in mean arterial pressure, which, in combination, led to a fall in systemic vascular resistance index versus BL (P < 0.001, each). In visceral organs, the trachea showed a significant increase in RMBF (P < 0.001). In addition, skeletal muscle significantly increased versus BL and versus controls over time (P < 0.01). Whereas the pancreas displayed a significant drop in RMBF versus BL and controls (P < 0.05), no statistical differences occurred in the renal cortex, spleen, and ileum. All investigated cerebral structures, such as the cortex cerebri, basal ganglia, thalamus, hippocampus, pons, medulla oblongata, and cerebellum showed a significant increase in RMBF versus BL and versus control animals (P < 0.05, each). These data differ in areas of normal, increased, and decreased RMBF during septic shock after smoke inhalation injury and show differences to former studies of our group investigating RMBF in ovine models of either smoke inhalation or P. aeruginosa infusion. The results of this study reflect the complex pathophysiological variances of the combined injury and may provide a basis for future investigations for the treatment of this kind of injury.