We hypothesized that inadequate oxygenation of peripheral tissues may be unrecognized in critically ill patients and may worsen their prognosis. To test this hypothesis, we measured oxygen delivery to tissues, oxygen uptake, and the extraction ratio (uptake/delivery) before and during a 30-minute infusion of a vasodilator, prostacyclin (5 ng per kilogram of body weight per minute), in 27 critically ill patients with acute respiratory failure. Prostacyclin produced an increase in oxygen delivery (median value before vs. during infusion, 375 vs. 492 ml of oxygen per minute per square meter of body-surface area, P less than 0.001) that was similar in the 14 patients who survived and the 13 who died. This increase in oxygen delivery was associated with a significantly greater increase in oxygen uptake in the patients who died as compared with the survivors (median increase, 19 vs. 5 percent, P less than 0.001). In the survivors, the oxygen extraction ratio fell (median change, -17 percent; range, -27 to -6 percent) and the mixed venous oxygen tension increased. In the patients who died, the extraction ratio rose (median change, 11 percent; range -24 to +40 percent) and the mixed venous oxygen tension did not change. These data suggest the presence of a substantial oxygen debt in patients who subsequently die. Inadequate tissue oxygenation, which may be difficult to recognize, appears to be an important mechanism contributing to the development of irreversible multiple organ failure and subsequent death in some patients with acute respiratory failure.