Purpose: 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. This study was conducted to assess the efficacy of the adjuvant use of misoprostol and oxytocin in decreasing intra-operative blood loss in cesarean delivery., Methods: This was a double-blinded randomized clinical trial including 636 term pregnant woman scheduled for cesarean section at Ain Shams University Maternity Hospital, Cairo, Egypt, between February 2013 and February 2014. Participants received either 400-μg misoprostol rectally or sublingually or placebo before cesarean section together with 5-IU oxytocin IV. The main outcome measure was intra-operative blood loss. Difference between the three groups was analyzed using one-way ANOVA test (for numeric variables) and Chi-square test (for categorical variables). P < 0.05 was considered statistically significant., Results: Intra-operative blood loss was higher in patients who did not receive misoprostol (Placebo Group) (295-1075 ml, 641.7 ± 135.7) than those who received it, regardless the route of administration, rectal (135-830 ml, 457.5 ± 140.7; P < 0.001), and sublingual (135-680 ml, 357.8 ± 129.7; P < 0.001). In addition, sublingual route was associated with significantly lower estimated intra-operative blood loss compared to rectal administration (P < 0.001)., Conclusions: Misoprostol with oxytocin is an effective drug-combination for decreasing intra-operative blood loss during cesarian section with clinical superiority to sublingual over rectal route.