This prospective, double-blind study was carried out to assess the usefulness of magnetic resonance imaging (MRI) as a noninvasive method in the diagnosis of chronic compartment syndrome (CCS). As well, a new radiopharmaceutical known as methoxy isobutyl isonitrile that has been shown to be taken up by muscle in direct proportion to its blood flow was used to illustrate the possible pathophysiology of this syndrome. Twenty patients with a history of chronic leg pain and possible diagnosis of CCS and five normal volunteers had preexercise and postexercise MRI, nuclear medicine imaging, and static and dynamic slit catheter pressure studies. Nine patients had classic symptoms; only five of these nine had abnormal pressure studies. The other 11 patients had an element of pain at rest and had normal pressure studies. The nuclear blood flow studies were normal in all 25 legs tested in this study. Measurement of intrinsic MRI parameters T1 and T2 in the normal legs as well as in those with an atypical history showed a marked elevation with exercise and a gradual return to baseline postexercise that was similar to the pressure curves. In the five patients with a clinical history and elevated pressures, four had abnormal MRI studies with failure of T1 to return to baseline values. Although these results demonstrate the potential of MRI as a tool for noninvasively monitoring muscle status, clinical history and examination remain important in the diagnosis of CCS. This study indicates that the pathophysiology of exertional compartment syndrome does not appear to be related to ischemia.