A prime factor in the thrombogenicity of synthetic materials in contact with blood is the blood-gas interface. Small pockets of gas, known as gas nuclei, are trapped within surface interstices. The resulting blood-gas interface denatures plasma proteins and activates clotting factors and platelets. Expanded polytetrafluoroethylene (ePTFE) vascular prostheses 1 mm in internal diameter were placed in saline under 6,000 psig hydrostatic pressure for 2 h in an attempt to dissolve all gas nuclei (i.e., to denucleate). Carotid-carotid bypasses were performed in rats using 280-mm lengths of ePTFE. All 10 control grafts lost patency in 5 min, whereas the 14 denucleated grafts had a median patency duration of 300 min (P less than 0.01). In 15-mm-long rat femoral artery interpositional ePTFE grafts, 90% of controls thrombosed within 10 min, whereas only 7% of denucleated grafts thrombosed over the duration of the 7-day observation period (P less than 0.001). Denucleation also resulted in a significant reduction (P less than 0.02) in 111In-labeled platelet adhesion to 36% of control. Scanning electron microscopy confirmed the reduced accumulation of platelets on denucleated grafts. These data suggest that the removal of trapped air with hydrostatic pressure significantly reduces the thrombogenicity of ePTFE microvascular prostheses and may have application to other clinical (catheters, valves, tubing, etc.) or experimental (micropipettes, electrodes, etc.) materials that interface with blood.