OBJECTIVE:: We evaluate the diagnostic performance of perfusion pressure (PP) thresholds for fasciotomy. DESIGN:: Prospective observational study. SETTING:: Seven Level-1 trauma centers.Patients/Participants: 150 adults with severe leg injuries and ≥ 2 hours of continuous perfusion pressure (PP) data who had been enrolled in a multicenter observational trial designed to develop a clinical prediction rule for acute compartment syndrome (ACS). MAIN OUTCOME MEASUREMENTS:: For each patient, a given PP criterion was positive if it was below the specified threshold for at least 2 consecutive hours. The diagnostic performance of PP thresholds between 10 and 30 mmHg were determined using two reference standards for comparison: 1) the likelihood of ACS as determined by an expert panel who reviewed each patient’s data portfolio, or 2) whether the patient underwent fasciotomy. RESULTS:: Using the likelihood of ACS as the diagnostic standard (ACS considered present if median likelihood ≥ 70%, absent if < 30%), a PP threshold of 30 mmHg had diagnostic sensitivity 0.83, specificity 0.53, positive-predictive-value 0.07, negative-predictive-value 0.99. Results were insensitive to more strict likelihood categorizations and were similar for other PP thresholds between 10- and 25-mm Hg. Using fasciotomy as the reference standard, the same PP threshold had diagnostic sensitivity 0.50, specificity 0.50, positive-predictive-value 0.04, negative-predictive-value 0.96. CONCLUSION:: No value of PP from 10-30 mm Hg had acceptable diagnostic performance, regardless of which reference diagnostic standard was used. These data question current practice of diagnosing ACS based upon PP and suggest the need for further research. LEVEL OF EVIDENCE:: Diagnostic Level I