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The purpose of this study was to evaluate the efficacy and safety profiles of topical tranexamic acid (TXA) in patients undergoing elective total knee arthroplasty (TKA) with comorbid conditions precluding them from intravenous (IV) TXA use. A total of 104 patients were divided into two groups: 47 in the normal-risk group and 57 in the high-risk group, with the latter representing those with one or more risk factors for venous thromboembolism (VTE). Demographics were similar between groups, and there were no differences with regard to postoperative changes in hemoglobin (− 3.42 g/dL ± 1.07 and − 3.68 g/dL ± 1.07, p = 0.214), total drain output (630.2 mL ± 331.6 and 566.9 mL ± 343.9, p = 0.344), postoperative transfusion rate (2.1 and 3.5%, p = 0.675), or total number of complications 3 (6.5%) and 5 (8.8%) for the normal- and high-risk groups, respectively (p = 0.671). Topical TXA exhibited a similar safety and efficacy profile in reducing postoperative blood loss in a group of patients at increased thromboembolic risk, without a significant increase in complications or thromboembolic events. Topical TXA appears to represent a safe and efficacious alternative to IV TXA in patients at high risk for VTE undergoing TKA.