Background: Prematurity is the leading cause of neonatal morbidity and mortality. Although perinatal care advanced in the last few decades, preterm labor did not decrease but even is increasing and creating a great social and economic problem. Objective: To test the effectiveness of progesterone vaginal suppository in prevention of preterm labor in patients with previous history of preterm labor. Patients and Methods: This  was a randomized ,  prospective, single blind study after approval of  the medical ethical committee at Al-Azhar  university  Hospitals, Department of Obstetrics and Gynecology,  and after patients giving written consents, during the period from February 2020 to October  2020 . We enrolled 168 women for the study at high risk for preterm labor who were randomly divided into two groups (progesterone group and placebo group). Two hundred mg of vaginal progesterone pessary or placebo were used by the patient from 24 to 36 weeks of gestation. Uterine contractions were recorded by external tocodynamometer every other week from 28 to 36 weeks of gestations. Results: There was a statistically significant reduction in the incidence of preterm delivery between the two groups from 38.5% in placebo group, compared with 21% in progesterone group. There was also a statistically significant reduction in the incidence of early preterm delivery (<34 week) between the two groups from 21.2% in placebo group, compared with 5.7% in progesterone group. There was a significant prolongation of the mean gestational age at delivery from 36.36 ± 2.83 weeks in placebo group compared to 37.57 ± 1.72 weeks in progesterone group. There was no statistically significant difference in the average gestational age for those who had preterm birth between both groups. There were fewer women in progesterone group who reported symptoms of preterm labor of 52.4%, compared with 75% in placebo group. There was a significant more frequent uterine contraction in placebo group of 48.1% compared to progesterone group of 24.8%. Conclusion: Prophylactic vaginal progesterone reduces the rate of preterm labor, prolongs gestational age at delivery, reduces the frequency of uterine contractions, and improves the symptoms of preterm labor in women at high risk of preterm labor.