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To assess the safety and efficacy of tranexamic acid (TXA) for decreasing perioperative blood loss in cervical laminectomy with lateral mass screw fixation and bone grafting (CLF), in which all surgical procedures are identical.From November 2014 to April 2016, we performed a retrospective comparative analysis of 119 patients with multilevel cervical spondylotic myelopathy who had undergone a CLF from C3 to C6 in our center. All surgeries were performed on the patients using a consistent, standard procedure. Patients were divided into control (46) and TXA (73) groups according to whether or not they had received TXA treatment before and during surgery. Demographic profiles of patients such as gender, age, body weight, height, and body mass index were collated and differences between the 2 groups compared. Preoperative and postoperative hematological data in addition to intraoperative and postoperative blood loss were compared between the 2 groups. Additionally, any complications of TXA were also evaluated to assess safety.There was no statistically significant difference in demographic traits between the 2 groups. Intraoperative blood loss in the TXA group (179.66 ± 81.45 mL) was significantly lower than that of the control group (269.13 ± 94.68 mL, P < 0.001), as was postoperative blood loss (108.08 ± 44.31 and 132.83 ± 49.39 mL, respectively; P = 0.005). Total blood loss in the TXA group (287.74 ± 115.40 mL) was also significantly lower than that of the control group (401.96 ± 127.88, P < 0.01). No major intraoperative complications occurred in any of the cases.TXA significantly reduced perioperative blood loss in CLF with no major side effects.