Multiple organ failure (MOF) is presently recognized as the most severe, and often lethal, complication after multiple trauma. Causal factors and pathomechanisms remain unclear, however. Generalized inflammatory cell tissue injury with a subsequent increase in permeability in all organs has been suggested. For this reason, 38 polytraumatized patients were examined in a prospective study. Organ function was analyzed, and specific clinical and histological studies were performed to check for generalized cell tissue damage and increased respiratory permeability. In all organs we found signs of tissue damage immediately after trauma. Disturbances of organ function were seen consistently, starting precisely from day 4. It was not possible to confirm an influence of blunt organ trauma on organ function during follow-up. The severity of injury (especially intrathoracic and intraabdominal) and massive bleeding increases the risk of MOF. MOF was not always associated with the onset of sepsis, and no temporal dependence could be shown. Histological studies demonstrated an inflammatory change in organ tissues, which is probably the result of toxic substances (endotoxin, TNF, oxygen radicals, proteases and eicanosoids) released into the blood circulation after trauma. Insufficient neutralization of these toxic metabolites leads to generalized permeability damage and consequently to progressive organ failure. Therefore, even with optimized initial treatment of multiple trauma patients, MOV and mortality can only be reduced with a causal approach to therapy.