Background <p>Placentas that are previa or low-lying are a major cause of severe postpartum hemorrhage (PPH). Tranexamic acid, by inhibiting the fibrinolytic pathway and protecting blood clots from degradation, is a promising drug for preventing blood loss after childbirth, especially in high-risk conditions. It remains unclear whether tranexamic acid would decrease the incidence of severe PPH among women with placentas that are previa or low-lying.</p> Methods and design <p>This multicenter, double-blind, randomized controlled trial with two parallel groups will include 1380 women with placenta previa or a low-lying placenta and a cesarean delivery at a term ≥ 32&#xa0;weeks, modeled on our previous study of tranexamic acid administered after cesarean deliveries (TRAAP2). Women with high antenatal suspicion of placenta accreta spectrum will not be included. Treatment (either tranexamic acid 1&#xa0;g or placebo) will be administered intravenously just after birth. All women will also receive a prophylactic uterotonic agent. The primary outcome will be the incidence of a red blood cell transfusion before discharge. This study will have a 90% power to show a 33% reduction in the incidence of transfusion, from 20.0% to 13.4%.</p> Discussion <p>This large multicenter, randomized placebo-controlled trial aims to determine with adequate power if the prophylactic use of tranexamic acid among women with cesarean delivery and a placenta that is previa or low-lying would decrease the incidence of transfusion.</p> Trial registration <p>ClinicalTrials.gov NCT04304625 (March 9, 2020).</p>