Background: Preterm birth (PTB) carries the greatest risk of perinatal morbidity and mortality because of its neurological and developmental consequences later in life.   
Objectives: To evaluate the efficacy and safety of vaginal progesterone alone or in combination with aspirin for the prevention of recurrent spontaneous PTB.   
Methods: This was a randomized, double blind, placebo controlled trial conducted on 256 pregnant females with previous history of spontaneous PTB who randomly di-vided into 2 groups; Group 1: 128 females received com-bined vaginal progesterone plus aspirin, and Group 2: 128 females received vaginal progesterone plus placebo started at 16-20 weeks' gestation. The primary outcome was the occurrence of PTB prior to 34 weeks' gestation. Secondary outcomes were maternal: (1) harm to the moth-er from intervention, (2) maternal infection or inflamma-tion, (3) prelabour rupture of membranes, (4) maternal mortality, and neonatal: (1) The gestational age at birth  (2) respiratory morbidity, (3) birth weight, (4) infection (neonatal sepsis), (5) gastrointestinal morbidity, (6) ear-ly neurodevelopmental morbidity (within one month of delivery), (7) harm to the neonate from intervention, (8) perinatal mortality.
Results: Both groups showed non-significant differ-ence regarding socio-demographic data. Rates of deliv-eries <34 weeks were 44% and 49% in group 1 and 2, respectively (p=0.072). Subgroup analysis according to the gestational age at delivery also done to detect if the drug combination (progesterone with aspirin) can have more effect at certain gestational age than others but the results were also non-significant. When considering other secondary outcomes, the rate of preterm rupture of mem-branes, neonatal birth weight, GIT morbidity, and perina-tal deaths all showed significant difference between both groups (p<0.05) with cases received both progesterone and aspirin had improvement of theses parameters. Conclusion: Combination of vaginal proges-terone and aspirin didn't significantly reduce the risk of recurrent spontaneous PTB than vaginal progesterone alone but had better neonatal outcomes by decreasing perinatal morbidity and mortality that might be sec-ondary to reducing the rate of preterm rup-ture of membranes.