Background: The objective of the present study was to compare the efficacy of intrauterine misoprostol with intravenous oxytocin infusion in reducing blood loss during and after cesarean section (CS).Methods: An open, randomized, clinical trial, registered (ClinicalTrials.gov ID: NCT03148574) conducted between July 1, 2017 and April 1, 2018. The study included 240 pregnant females that were recruited at term (37-40 weeks) gestation scheduled for either elective or emergency CS. Eligible participants were randomly allocated into two equal groups: Group A: patients who receive intravenous infusion of 10 I.U diluted to 500ml of normal saline for 30 minute after delivery. Group B: patients received 400μg misoprostol intrauterine just after cord clamping and delivery of the placenta. Primary outcome measure was assessment of amount of intraoperative and postoperative blood loss.Results: The intraoperative and 2h postoperative blood loss in the misoprostol group was higher than oxytocin group (p<0.001). Hemoglobin level decreased significantly among both groups, manifested by the highly significant p value in comparison of pre and postoperative Hb level in the two groups (p<0.001). However, the blood loss in the misoprostol group was higher than oxytocin group (p=0.004). There was a statistical significant differences between both groups as regards the need for additional uterotonic drug (66% in misoprostol group vs 5% in oxytocin group, P<0.001). Shivering and pyrexia were more in common in the misoprostol group while vomiting, headache and giddiness were significantly higher among oxytocin group.Conclusions: Administration of misoprostol 400mcg through intrauterine route appears to be less effective than intravenous oxytocin infusion in reducing blood loss during and after CS.