Background Topical hemostatic agents composed of a gelatin-based matrix and thrombin have been reported to be effective, in addition to traditional means, in terminating bleeding during cardiac operations. We compared a hemostatic matrix sealant agent (FloSeal; Baxter Inc, Deerfield, IL) with alternative topical hemostatic agents in a mixed cohort of elective cardiac and thoracic aortic operations. Methods Following sample size calculation, in a prospective randomized study design, 209 patients were treated with FloSeal matrix sealant (FloSeal group) and 206 patients received alternative agents as topical hemostatic materials (comparison group). FloSeal is composed of a self-expandable gelatin matrix component and purified bovine thrombin. Comparisons included hemostatic patches or sponges composed of either oxidized regenerated cellulose or purified porcine skin gelatin. Study endpoints were the following: rate of successful intraoperative hemostasis (identified by cessation of bleeding) and time required for hemostasis; overall postoperative bleeding; rate of transfusion of blood products; rate of surgical revision for bleeding; postoperative morbidity; and intensive care unit stay. Results Statistically higher rates of successful hemostasis and shorter time-to-hemostasis were observed in the FloSeal group ( p < 0.001 both). Time-to-event analysis confirmed this finding ( p = 0.0025). Postoperative bleeding and rate of transfusion of blood products were statistically decreased in the FloSeal group ( p < 0.001 both). Rates of revision for bleeding and of minor complications were not statistically different among groups in the overall cohort, but were significantly lesser in the FloSeal group if only patients with overt intraoperative bleeding are considered ( p = 0.04 both). The advantages observed in the FloSeal group were not offset in patients undergoing systemic hypothermia. Conclusions The topical hemostatic agent used in the FloSeal group is effective in terminating intraoperative bleeding as an adjunct to traditional surgical methods for stopping bleeding. Its judicious use is associated with lesser need for transfusion of blood products and rate of revision for bleeding. Its cost-utility profile should be addressed in dedicated trials.