Abstract: Background: The commonest surgical procedure for women is cesarean delivery. Postpartum hemorrhage and intra-operative blood during cesarean delivery is a major concern to all obstetricians. Aim: This study aims at comparing the efficacy of combined use of rectal misoprostol and oxytocin infusion with oxytocin in the prevention of PPH in cesarean delivery. Materials and Methods: This was a prospective comparative observational study including 180 term pregnant woman scheduled for cesarean section at Tishreen University Hospital, Lattakia, Syria, between December 2020 and December 2021. Participants were divided into two equal groups. One group was treated with 20-IU oxytocin IV infusion alone while the other group was treated with Tab. Misoprostol 800mcg, rectal route plus 20-IU oxytocin IV infusion. The main outcome measure was postoperative blood loss. Results: Both groups were comparable with regard to the age, parity, gravidity, and gestational age as well as hemoglobin and hematocrit levels. The combined use of rectal misoprostol plus oxytocin, compared with the use of oxytocin alone, was associated with a significant reduction in the mean blood loss (418 ± 150 ml vs. 649 ± 214 ml, respectively, P<0.0001), and a significant reduction in the mean decrease in hemoglobin and hematocrit. Moreover, the needs for a blood transfusion or extra uterotonics were significantly lower in the combination group than in oxytocin group (p<0.05). The use of rectal misoprostol combined with oxytocin was associated with a statistically significant increase in the rates of fever.