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Objectives: Orthognathic surgery is a corrective intervention for maxillofacial deformities. Bleeding is a major concern for oral and maxillofacial surgeons. Various agents, such as hemocoagulase, tranexamic acid, and aprotinin have been developed to reduce intraoperative bleeding and transfusion requirements. Therefore, in this study we aimed to investigate the effects of hemocoagulase and tranexamic acid, as well as their simultaneous use, to reduce bleeding during orthognathic surgery. Patients and Methods: This retrospective study included patients who had undergone simultaneous orthognathic surgery of the maxilla and mandible between January 2013 and September 2022 and were classified into three groups based on drugs administered: hemocoagulase (Botropase), tranexamic acid, and a combination of both drugs. We recorded patient age, sex, weight, blood loss, and duration of surgery. Red blood cell (RBC), hemoglobin, hematocrit, and platelet levels were measured before, immediately after, and one day after surgery. Results: No statistically significant differences were found in blood loss, RBC, hemoglobin, hematocrit, or platelet levels between any of the groups. There were no differences in the drug effects between Le Fort I and bilateral mandibular sagittal split osteotomies, with or without double genioplasty. However, there were significant reductions in RBC, hemoglobin, hematocrit, and platelet levels during genioplasty. Conclusion: Tranexamic acid, hemocoagulase, and their combination had similar efficacy in patients who underwent Le Fort Ⅰ and bilateral mandibular sagittal split osteotomies with and without genioplasty.