Background <p>Tranexamic acid (TXA) has been increasingly acknowledged as a beneficial pharmacological agent in plastic surgery. However, despite its proven efficacy and safety, there is limited research on its intravenous application in gender-affirming mastectomy, particularly regarding its effect on drain duration, drain output, and length of hospital stay.</p> Methods <p>In this retrospective single-center study, patients who underwent double incision mastectomy with free nipple grafts were categorized into two cohorts: one group receiving TXA and a control group without TXA utilization (TXA vs no-TXA). Demographic characteristics, surgical data, and complication rates were analyzed and compared.</p> Results <p>A total of 75 patients were included, with 34 procedures performed without the administration of TXA and 41 patients receiving TXA. The median age of the study population was 24 years (range 18–57). Postoperative bleeding requiring surgical revision was significantly less frequent in the TXA group (<i>p</i> = 0.038). Total drain output (<i>p</i> = 0.048), drain duration (<i>p</i> &lt; 0.001) and length of hospital stay (<i>p</i> = 0.008) were significantly reduced in the TXA group. No thromboembolic events or seizures were observed.</p> Conclusions <p>This study demonstrated that intravenously administered TXA significantly reduces the incidence of postoperative hematoma, length of hospital stay, drain duration, and output after gender-affirming mastectomy. Based on these findings, we would recommend the use of TXA in double incision mastectomy with free nipple grafts to minimize the occurrence of seroma formation and major bleeding-related complications.</p> Level of Evidence IV <p>This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors &#xa0;<a href="http://www.springer.com/00266">www.springer.com/00266</a>.</p>