Introduction: Despite ongoing optimisation of surgical techniques, hemostasis continues to be a fundamental challenge in many operations today. This randomised controlled trial compared the efficacy of a new hemostatic agent made of oxidised regenerated cellulose and collagen (ORC-Coll) with that of a conventional carrier-bound fibrin sealant (CBFS). Methods: Hemostasis was investigated representatively in the case of post-thyroidectomy bleeding from the resection surface. To demonstrate that ORC-Coll (mediCipio® A) has at least the same hemostatic efficacy as CBFS (Tachosil®), the volume of drainage fluid at the time of drain removal was used as the primary endpoint in a non-inferiority test with a significance level of 5%. The secondary endpoints included number and size of hemostatic agents required, adhesion of the hemostatic agent to the bleeding surface, intraoperative hemostatic effect, duration of drainage and adverse events during a six-month follow-up period. Results: A total of 150 patients (ORC-Coll: 75; CBFS: 75) were included. After operation, total volume of drainage fluid was 68.20 ± 44.56 mL in the ORC group and 68.21 ± 40.20 mL in the CBFS group. The non-inferiority of ORC-Coll compared to CBFS with regard to hemostatic efficacy was shown at a significance level of 5%. The results demonstrated effectiveness in achieving hemostasis without adverse events. Conclusions: ORC-Coll is an effective hemostatic agent and barrier sealant without blood components, which ensures reliable prevention of intra- and postoperative bleeding. With use of the new technique, any risks associated with the use of human blood components are a priori eliminated.