In the passive upright position, arterial and venous pressure in human feet increases capillary pressure, which leads to the filtration of fluid from the circulating plasma into the tissues of the feet. Loss of fluid concentrates both red cells and plasma so that the hematocrit and plasma protein concentration of venous blood leaving the feet greatly exceed their mean values in the circulation. To study this phenomenon in animals, the authors used beagle dogs maintained in an upright position and compared the results to those maintained in a prone position. In the passive upright position, red cell count, hematocrit, and total plasma protein concentrations were significantly increased. Therefore, we have determined the level of hydroxyl free radical formed as assessed by salicylate hydroxylation in the saphenous vein of dogs in an upright and normal position. Hydroxyl free radical formation was significantly higher in the veins of dogs in an upright position than in those in a prone position. The upright position model, which causes increases in hematocrit red cell count and total plasma protein in the saphenous vein, seems suitable for the study of drugs interfering in the pathophysiology of venous stasis. Indeed, the hematocrit increase of red cell count and total plasma protein in the saphenous vein of the beagle is similar to modifications observed in venous blood leaving the human foot after sitting. Moreover, the increase of .OH, concomitant with these modifications, may explain certain pathological observations, for instance, edema. The data clearly suggest that macromolecular extravasculation may be due to tissue injury caused by oxygen free radical formation in the blood vessels.