Hypothesis: A novel collagen-based composite of bovine microfibrillar collagen and bovine thrombin combined with autologous plasma is more effective than standard hemostasis (collagen sponge applied with pressure) in controlling diffuse hepatic bleeding after hemihepatectomy or segmental resection of the liver. Design: Randomized controlled trial. Setting: Seven university-affiliated medical centers. Patients: Sixty-seven adult patients scheduled for hemihepatectomy or segmental resection who received hemostatic intervention with an investigational treatment (n = 38) or control (n = 29). Intervention: Bleeding hepatic tissue was managed in all control subjects with a collagen sponge with manual pressure. Subjects in the experimental group had the sprayable liquid composite intraoperatively applied to the surgical site. The liquid immediately formed a collagen-fibrin gel that was used without concomitant tamponade. Main Outcome Measures: Hemostatic success was defined as the proportion of subjects in each treatment group who achieved complete hemostasis within 10 minutes. Success rates and median times required to achieve controlled bleeding (ie, slight oozing) and complete hemostasis were compared between treatment groups. Results: All 38 subjects in the experimental group achieved complete hemostasis within 10 minutes compared with only 69% (20/29) of control subjects (P<.001). The median time to controlled bleeding was approximately 4 times longer (250 vs 62 seconds) for control subjects than for experimental group subjects (P<.001). The median time required to achieve complete hemostasis also favored the experimental group (150 vs 360 seconds; P<.001). No adverse events related to the use of the experimental hemostatic agent were detected. Conclusions: The experimental composite is more effective at controlling and stopping diffuse hepatic bleeding than a collagen sponge applied with pressure; it may be a useful hemostatic agent for patients undergoing hemihepatectomy, segmental resection, and related surgical procedures.