Background: Twins constitute 2-4% of all births and the rate of twining has increased by 76% between 1980 and 2009.Twin pregnancies, compared with singletons, are at increased risk for fetal anomalies, preterm births, aberrant fetal growth, cerebral palsy and perinatal and infant mortality. Maternal complications associated with twin pregnancies include hypertensive disorders, gestational diabetes, cesarean delivery, postpartum hemorrhage and maternal mortality.  Aim of the Work: This study aimed to assess the efficacy of vaginal progesterone compared to intramuscular therapy in  decreasing the rate of preterm birth in women with twin pregnancies.  Patients and Methods: This randomized controlled trial included women presented to Ain- Shams University Maternity Hospital. The study presented for approval from the Ethical Committee of the Department of Obstetrics and Gynecology, Faculty of Medicine, Ain-Shams University. Informed consent was signed after explaining the study purpose and methods to the subjects. Data presentation did not include the patient name, but diagnosis was included.  Results: There was no statistically significance between the two groups regarding number of neonatal RDS, NICU admission and neonatal death. Birth weight was significantly higher among vaginal group. NICU stay was significantly higher among intramuscular group.  Conclusion: Compared with intramuscular 17-OHPC, vaginal progesterone in women with twin pregnancy is associated with lower percentage of preterm labour, less recurrent spontaneous preterm birth, less adverse maternal side effects, fewer NICU admissions and better compliance.