Background. Intraoperative bleeding is ubiquitous during open surgical procedures and uniformly effective hemostasis remains elusive. We conducted a randomized controlled trial to determine the effectiveness of a novel collagen-based composite (CoStasis Surgical Hemostat) compared with standard methods of hemostasis during general, hepatic, cardiac, and orthopedic operations. Methods. Hemostatic treatment was assigned randomly to 347 subjects; 318 subjects (167 CoStasis, 151 controls) underwent operation, received treatment, and provided hemostatic success data. CoStasis was applied to the bleeding site without manual pressure as a sprayable liquid composite of bovine microfibrillar collagen, bovine thrombin, and autologous plasma. Manual compression was used as the control hemostat. Hemostatic success was achieved if bleeding had ceased completely within 10 minutes (3 minutes for cardiac subjects). The time to controlled bleeding (ie, slight oozing) and time to complete hemostasis were recorded for all subjects. Results. Hemostatic success was achieved in more than 90 % (153/167) of CoStasis subjects compared with 58% (88/151) of control subjects (P = .01). Superior hemostatic effectiveness with CoStasis was realized in every surgical specialty: general (77/79 vs 49/75, P = .01), hepatic (38/39 vs 20/29, P = .01), cardiac (28/37 vs 17/37, P = .02), and orthopedic (10/12 vs 2/10, P = .01). The duration of bleeding was also significantly shorter with CoStasis. The median time to controlled bleeding (42 seconds vs 150 seconds, P =. 0001) and time to complete hemostasis (75 seconds vs 252 seconds, P = .0001) were both markedly longer with the control intervention. There were no serious adverse events related to the use of CoStasis. Conclusions. CoStasis is more effective at controlling and stopping diffuse intraoperative bleeding than standard methods of hemostasis in 4 distinct surgical indications representing a wide variety of operative interventions.