OBJECTIVE To compare maternal morbidity before and after implementation of a postpartum hemorrhage (PPH) protocol that included misoprostol. METHODS A retrospective analysis was performed using data from 34 631 deliveries recorded at a Spanish hospital between January 1, 2007, and December 31, 2014. The PPH protocol was implemented in 2009 and included use of misoprostol and the Bakri balloon. RESULTS The pre-implementation and post-implementation groups comprised 9394 and 25 237 women, respectively. Women in the pre-implementation group tended to have lower hemoglobin levels than did those in the post-implementation group: 811 (8.6%) versus 1349 (5.3%) for levels less than 90 g/L, and 272 (2.9%) versus 497 (2.0%) for levels less than 80 g/L (both P<0.001). Implementation of the PPH protocol was also associated with a decrease in the frequency of postpartum hysterectomies owing to uterine atony (0.11 cases per 1000 deliveries vs 0.53 cases per 1000 deliveries for the pre-implementation group; P=0.063). Pregnancy length, maternal age, neonatal weight at delivery, multiple pregnancy, previous cesarean delivery, parity, operative vaginal delivery, induced labor, cesarean delivery, and not using the PPH protocol were found to predict postpartum anemia in the multivariate analysis (all P<0.001). CONCLUSIONS Implementation of the PPH protocol decreased rates of postpartum anemia and postpartum hysterectomy owing to uterine atony.