Experimental models of deep venous thrombosis, heretofore, have not been available for laboratory studies. This investigation establishes a novel model of venous thrombosis by inhibiting the protein C system combined with venous stasis and subtle venous injury. Ten adolescent baboons were studied in pairs, with one animal receiving saline solution (B2, B4, B6, B8, B10) and one being exposed to thrombogenic reagents (B1, B3, B5, B7, B9). These reagents represented a combination of a monoclonal antibody (HPC₄) to protein C, 1 to 4 mg/kg administered over 5 minutes, and tumor necrosis factor administered over 3 minutes at a dose of 150 μg/kg through a catheter placed into the left superficial femoral vein with distal ligation. To encourage stasis, a pediatric size blood pressure cuff was inflated to 40 mm Hg on the right thigh for 50 minutes of every hour during the first experimental day (day 1) in B5 to B10. The animals were observed for a 6-hour period on day 1 and then for an 11- to 15-day period until sacrifice. Hemodynamic and hematologic parameters were recorded along with duplex imaging of the iliac veins and inferior vena cava on a daily basis. Venography was performed on day 1, day 4, and the day of sacrifice. At sacrifice the entire iliac and vena caval system was carefully dissected, opened, and photographed. Experimental animals given the HPC₄ and tumor necrosis factor developed left iliac vein thrombosis extending into the inferior vena cava. Duplex imaging, venography, and autopsy revealed that control animals receiving saline solution never developed comparable thrombus. Experimental subjects exhibited thrombus on duplex imaging by day 4 (B1), day 3 (B3), day 2 (B5), 120 minutes (B7), and 360 minutes (B9) after receiving HPC₄ and tumor necrosis factor. Venograms performed on day 1 exhibited thrombus in B5, B7, and B9. The extent of thrombus, the timing of its occurrence, and its effect on the animals' left leg followed a dose-dependent relationship for the animals in which the occlusive blood pressure cuff was used. Significantly greater declines in blood pressure, white blood cell count, and platelet count were found in affected animals given HPC₄ and tumor necrosis factor reagents as compared to control subjects. All affected animals demonstrated the appearance of fibrin split products and a markedly prolonged prothrombin time. This investigation, for the first time, establishes a reproducible model of deep venous thrombosis involving inhibition of protein C that will facilitate further laboratory studies on venous thrombosis.