Sepsis is characterized by decreased microcirculatory flow and increased peripheral shunting. Previous studies have shown red blood cell deformability (RCD) is decreased during sepsis. The purpose of this study was to evaluate the effect of changes in RCD on hemodynamics and oxygen utilization during sepsis. RCD, arteriovenous oxygen difference (DA-VO2), mixed venous oxygen saturation (MVO2), intrapulmonary shunt (QS/QT), cardiac index, and systemic vascular resistance were measured in 10 trauma patients, all of whom had or developed clinical sepsis. Data are expressed as mean +/- SD. Patients with normal RCD (> 0.75) were compared with those with low RCD (< 0.75). Patients with low RCD had a significantly higher incidence of sepsis (100% vs. 20%, P < 0.05, Student's t test or Fisher's Exact Test), lower DA-VO2 (2.4 +/- 0.9 vs. 4.8 +/- 1.5 P < 0.05, Student's t test or Fisher's Exact Test), and higher MVO2 (79 +/- 8 vs. 65 +/- 11 P < 0.05, Student's t test) or Fisher's Exact Test) than those patients with normal RCD. There was a direct correlation between RCD and DA-VO2 (r = 0.852, P < 0.001). MVO2 correlated inversely with changes in RCD (r = 0.813, P < 0.001). No significant correlation existed between RCD and cardiac index or systemic vascular resistance. Patients with low RCD demonstrated impaired oxygen utilization; changes in RCD correlated closely with changes in DA-VO2 and MVO2. These data suggest that decreased RCD may have an etiologic role in the impaired oxygen utilization that occurs during sepsis.