To compare the effectiveness of prophylactic carbetocin with prophylactic oxytocin for preventing severe postpartum hemorrhage (PPH) following vaginal delivery. This before and after cohort study took place between 2020 and 2021 in a university maternity hospital. In 2021, the protocol for PPH prevention immediately after vaginal delivery changed: intravenous oxytocin (5 IU) was replaced by intravenous carbetocin (100 μg). All patients with vaginal births were included, with two groups compared: patients who received prophylactic oxytocin in 2020 and those who received prophylactic carbetocin in 2021. The primary outcome was severe PPH, defined as one or more of the following: estimated blood loss ≥1500 mL, transfusion ≥4 units of red blood cells, Bakri balloon use, embolization, vascular ligation, hysterectomy, and maternal death. Among 4832 women included, 2417 received oxytocin and 2415 received carbetocin. The rate of severe PPH was similar in both groups (0.5% vs. 0.6%, respectively; adjusted odds ratio, 0.8 [95% confidence interval, 0.4-1.8]). The rate of PPH ≥500 mL was lower in the carbetocin group (4% vs. 5.8%; P = 0.004). Although prophylactic carbetocin was associated with a reduction in the rate of PPH ≥500 mL, carbetocin is no different to oxytocin in preventing severe PPH caused by atony after vaginal delivery. © 2023 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.