Background: Postpartum hemorrhage (PPH) or excessive bleeding at or after childbirth is a potentially life-threatening complication and is one of the major contributors to maternal mortality and morbidity worldwide. Objective: To compare the effect of IV Carbetocin and Rectal Misoprostol to decrease blood loss in third stage of vaginal delivery in low risk patients for postpartum hemorrhage. Patients and Methods: A randomized controlled trial was performed at Beni Suef Specialized Hospital in Obstetric Unit. The study included 160 healthy women with viable normal singleton pregnancy achieving normal vaginal delivery at or beyond 37 gestations from March 2019 till August 2019. Women were randomized to receive either a single dose Of Carbetocin 100 mcg following delivery of the anterior shoulder of baby or rectal misoprostol 800 mcg (4 tabs) at the crowning in the second stage of labor. Results: There was non-statistically significant difference in the estimated mean blood loss between the carbetocin and misoprostol groups with blood loss of 203 ml higher in misoprostol group. The mean drop of hemoglobin concentration 12h after delivery was 0.63g/dl in carbetocin group and 1.1g/dl in misoprostol group and drop in hematocrit value was 1.9% in carbetocin group and 3.3% in misoprostol group. These differences were statistically non-significant in both groups. Women in the carbetocin group were more likely to experience abdominal pain than misoprostol group. Headache and tachycardia were predominate in carbetocin group, women needed other uterotonic drugs more in misoprostol group. Blood transfusion was needed in some misoprostol group cases. Conclusion: Single dose of carbetocin 100 mcg was with the same effect to 800 mcg (4 tablets) misoprostol to decrease blood loss in third stage of normal vaginal delivery of low risk patients for postpartum hemorrhage, with no significant drop in hemoglobin and hematocrit in two groups but with more side effects and more cost in carbetocin group than misoprostol group.