Postpartum hemorrhage (PPH) is an obstetrical emergency that occurs in 1% to 10% of all deliveries and contributes to nearly one-quarter of all maternal deaths worldwide. Tranexamic acid has been established as an adjunct in the treatment of PPH but its role in its prevention of PPH following vaginal delivery has not been widely studied. This study aimed to assess the effect of prophylactic tranexamic acid (1 g) along with active management of the third stage of labor in reducing postpartum blood loss and the incidence of postpartum hemorrhage after vaginal delivery. In this randomized controlled trial, 650 women with singleton pregnancies at ≥34 weeks of gestation who were undergoing vaginal delivery were included. Eligible women were randomly assigned to receive either 1 g of tranexamic acid or placebo intravenously along with active management of the third stage of labor. Calibrated blood collection bags were used to measure postpartum blood loss during the third and fourth stages of labor. Of 886 women approached for the study, 650 who met the inclusion criteria were enrolled, and 320 in group A and 321 in group B were analyzed. The maternal characteristics were similar between the groups. The mean blood loss did not differ significantly between the intervention and placebo groups (378.5±261.2 mL vs 383.0±258.9 mL; P=.93). The incidence of primary postpartum hemorrhage was comparable in both groups (15.9% in group A and 15.3% in group B; P=.814). The median quantitative decreases in hemoglobin levels within 12 to 24 hours after delivery were 0.60 g% (interquartile range, 0.40-0.90) in group A and 0.60 g% (interquartile range, 0.40-0.80) in group B, which were comparable in both groups (P=.95). The most common adverse effect reported was dizziness, and there was no thromboembolic event at 3 months follow-up in either group. The use of tranexamic acid as a prophylactic measure along with active management of the third stage of labor does not provide additional benefit in reducing the postpartum blood loss and incidence of postpartum hemorrhage after vaginal delivery. El resumen está disponible en Español al final del artículo.