Background: Uterine leiomyomas are highly prevalent benign monoclonal tumors, arising from the smooth muscle of the myometrium; they occur in up to 50-60% of reproductive age women, causing significant morbidity in up to 30% of women. The most serious complication of uterine fibroids; is red degeneration that causes severe pain, and may lead to preterm labour, miscarriage, fetal and maternal morbidity and mortality. Objective of this study was designed to compare between the effect of vaginal natural MP and oral dydrogesterone in prevention of red degeneration of uterine fibroid during pregnancy.Methods: Patients were recruited from El-Shatby Maternity University Hospital. They were 50 pregnant females, diagnosed having a uterine fibroid more than 3 cm in size then there were divided into two groups, Group A: twenty-five treated by vaginal natural progesterone, Group B: twenty-five treated by oral dydrogesterone. All patients at 14-15 weeks of gestational age underwent complete history taking, clinical examination and ultrasound examination for mean gestational age and assessment of the type and uterine fibroid.Results: Results showed that there were no statistically significant differences as regards age, obstetric history (gravidity and parity), number, Site, grade and size of the fibroid. There was a significant difference between the two studied groups, regarding the acute abdominal pain, it occurred to only 3 cases (12%) in Group A, versus to 16 cases (64%) in Group B. Regarding occurrence of red degeneration, it occurred only to 3 cases (12%) in Group A, while in Group B it occurred to 15 cases (60%).Conclusions: Vaginal natural micronized progesterone is more effective than oral dydrogesterone in prevention of red degeneration of uterine fibroid in pregnancy with fewer complications. Vaginal natural progesterone daily dose of 200 mg is recommended to all pregnant females with uterine fibroids.