Extensive muscle crush injury culminating in the crush syndrome (CS) is often lethal unless promptly and vigorously treated. The causes of death in the CS are extreme hypovolemic shock, hyperkalemia, hypocalcemia, metabolic acidosis, acute myoglobinuric renal failure, and the compartment syndrome. Treatment consists of early massive volume replacement, preferably administered in the field, followed by forced alkaline solute (mannitol) diuresis. With this regimen, it is possible to increase substantially the survival of lives and limbs and to prevent acute myoglobinuric renal failure in patients suffering from the CS. Preliminary experience suggests that intravenous hypertonic mannitol is protective also to the injured muscle and can be used as a noninvasive adjunct in the management of compartment syndrome in humans. Moreover, by preserving muscular integrity, mannitol can conceivably reduce sarcolemmal leakage of the nephrotoxic myoglobin urate and phosphate and thus further defend kidney function. Furthermore, mannitol reduces the plasma pool of these nephrotoxic metabolites by increasing urinary elimination.