To assess the role of high-energy phosphate compounds in the etiology of heat injury with respect to the release of intracellular constituents, the susceptibility of selected tissues to heat injury, and the shock-like demise of the animals, rats were exercised on a treadmill (9.14 m/min) in a hot environment (34.5-35 degrees C) to a rectal temperature (Tre) of 42.5-43 degrees C. In the heart, kidney, left lateral lobe of the liver, and gastrocnemius muscle extricated from animals immediately upon termination of the treadmill run, levels of glucose-6-phosphate (G-6-P), adenosine triphosphate (ATP), and creatine phosphate (CP) were unchanged when compared with sedentary controls. In animals which had been resuscitated by infusion of isotonic saline into a jugular catheter, levels of CP were significantly (p less than 0.025) elevated in gastrocnemius muscle. In rats which were unconscious and succumbing to the effects of hyperthermic injury, levels of hepatic G-6-P and ATP were significantly reduced (p less than 0.05, p less than 0.02, respectively). These results indicate that the combination of exhaustive excercise/heat injury had the most deleterious effects upon hepatic metabolism. However, while resuscitation with physiological saline may be accompanied by an increased synthesis of CP, hyperthermic exhaustion and the concomitant efflux of cellular constituents cannot be attributed to a depletion or even a decrement of high-energy phosphates in vital tissues.