PurposeThis study aimed to evaluate the safety of total knee arthroplasty (TKA) in Jehovah’s Witness patients compared to non-Jehovah’s Witness patients using standard peri-operative TKA protocols as well as assess the role of tranexamic acid (TXA) in managing blood loss in this population. MethodsPatients undergoing TKA between 2011 and 2021 at two tertiary academic centers were retrospectively reviewed. Patient demographics, pre- and post-operative hematologic laboratory values, intra-operative tranexamic acid use, 90-day post-operative complications, and subsequent revisions were collected. These variables were then compared between propensity score-matched cohorts at a 2:1 ratio of those who did not identify as Jehovah’s Witness to those who did. Regression analysis was used to determine the effect of intraoperative TXA on hemoglobin (hgb) shift. ResultsAfter applying exclusion criteria and matching, the TKA outcomes of 316 non-Jehovah’s Witness patients and 152 Jehovah’s Witness patients were analyzed. Univariate analysis suggested that non-Jehovah’s Witness patients and Jehovah’s Witness patients had similar pre- and post-operative hgb, hgb shift, and hematocrit (hct). Only 1 (0.8%) Jehovah’s Witness patient reached a hgb < 8.0 mg/dL post-operatively. Multivariate logistic regression suggested that Jehovah’s Witness patients did not have increased odds of reaching a hgb < 8.0 mg/dL (odds ratio [OR] = 0.99 [0.96, 1.02]; P = 0.42). Multivariate linear regression suggested that intra-operative TXA was positively correlated with hgb shift and thus a smaller decrease in hgb from pre- to post-TKA (β = 0.38 [0.06, 0.69]; P = 0.02). Additionally, Jehovah’s Witness patients had excellent revision-free (95% [91, 99]) and infection-free (98% [95, 100]) survival at 8 years. ConclusionStandard peri-operative TKA protocols are safe for Jehovah’s Witness patients who do not have the need for transfusion, especially with appropriate pre-operative hgb levels and the use of intra-operative TXA. Furthermore, these patients have excellent survivorship at 5 and 8 years follow-up.