Background: This study intended to evaluate the safety and hemostatic efficacy of a novel vascular sealant (Tridyne; Neomend, Inc, Irvine, CA) compared with an accepted adjunctive hemostatic agent applied to aortotomy and sutures lines in cardiovascular operations. Methods: Patients undergoing aortic valve replacement, ascending aortic replacement, or aortic root replacement were randomly assigned 2:1 to Tridyne (n = 107) or Gelfoam Plus (Baxter Healthcare Corp, Hayward, CA) (n = 51). These groups were similar with regard to age, sex, race, medical history, duration of bypass and cross-clamping, and number of suture lines treated. Suture lines were treated after confirmation of some leakage but before formal removal of the clamp. Results: The median bleeding time was significantly lower for Tridyne versus Gelfoam Plus (0 versus 10.0 minutes, p < 0.0001). Immediate hemostasis was achieved in 59.4% of the Tridyne group versus 16.0% of Gelfoam Plus group (p < 0.0001). A significantly greater proportion of patients in the Tridyne group achieved successful hemostasis at the aortic suture line than patients in the Gelfoam Plus group (85.7% versus 40.0%, p < 0.0001). The Clinical Events Committee adjudicated 7 patients with possible device-related serious adverse events: 3 patients (2.9%) in the Tridyne group and 4 patients (8.2%) in the Gelfoam Plus group (p = 0.2097). Conclusions: Tridyne was safe and effective when used as an adjunct to conventional hemostasis to treat high-pressure vessels in patients who receive anticoagulation agents, in reducing time to hemostasis, and in promoting both immediate and persistent hemostasis.