The change in tissue PO2 in response to an increased inspired O2 challenge may be related to the state of cellular oxygenation, and hence the adequacy of resuscitation. To test this hypothesis, we measured tissue PO2 during inspired O2 challenges in 29 injured patients during acute resuscitation or intensive care unit monitoring. The O2 challenge test had 100% sensitivity and specificity in detecting flow-dependent O2 consumption in invasively monitored patients in the intensive care unit. During acute resuscitation, 60% of patients had negative initial O2 challenge test results, indicating that flow-dependent O2 consumption might have been present. Of nine such patients, five had subsequent positive O2 challenge test results after fluid resuscitation, indicating successful resuscitation. Four patients (27% of acute resuscitations), however, had repeatedly negative findings, possibly indicating persistent inadequate cellular oxygenation despite fluid resuscitation. Other commonly measured variables did not differentiate these patients. Monitoring of tissue PO2 during an inspired O2 challenge may be a useful test for determining the adequacy of resuscitation from hypovolemic shock.