The diagnosis of acute compartment syndrome (ACS) is a common clinical challenge among patients who sustain high-energy orthopaedic trauma, largely because no validated criteria exist to reliably define the presence of the condition. In the absence of validated diagnostic standards, concern for the potential clinical and medicolegal impact of a missed compartment syndrome may result in the potential overuse of fasciotomy in “at-risk” patients. The goal of the Predicting Acute Compartment Syndrome Study was to develop a decision rule for predicting the likelihood of ACS that would reduce unnecessary fasciotomies while guarding against potentially missed ACS. Of particular interest was the utility of early and continuous monitoring of intramuscular pressure and muscle oxygenation using near-infrared spectroscopy in the timely diagnosis of ACS. In this observational study, 191 participants aged 18–60 with high-energy tibia fractures were prospectively enrolled and monitored for up to 72 hours after admission, then followed for 6 months. Treating physicians were blinded to continuous pressure and oxygenation data. An expert panel of 9 orthopaedic surgeons retrospectively assessed the likelihood that each patient developed ACS based on data collected on initial presentation, clinical course, and known functional outcome at 6 months. This retrospectively assigned likelihood is modeled as a function of clinical data typically available within 72 hours of admission together with continuous pressure and oxygenation data. This study will improve our understanding of the natural history of compartment syndrome and examine the utility of early and continuous monitoring of the physiologic status of the injured extremity in the timely diagnosis of ACS.