Background: The primary cause of newborn morbidity and death is preterm birth (birth before 37 weeks gestation) which carries a substantial economic burden to health care and social services. Objective: This study aimed to assess the efficacy of low dose of aspirin and vaginal progesterone in prevention of preterm birth. Patients and Methods: This is randomized controlled clinical trial on 127 pregnant womenthat was conducted at Obstetrics and Gynecology Department in Samanoud General Hospital at El Gharbia Governorate, which was held from October 2020 to June 2022. Results: There was a significant difference between aspirin, progesterone and combination groups regarding early preterm birth <34 weeks (P= 0.024). While there were no significant differences among the studied groups regarding preterm birth <37 weeks (P> 0.05). Conclusion: Vaginal progesterone with low-dose aspirin, starting at 14-16 weeks gestation and continuing until 36 weeks, can considerably lower the incidence of preterm delivery < 34 weeks. Aspirin and vaginal progesterone are safe drugs in pregnancy.