Background: Miscarriage is the loss of a pregnancy before the period of viability. In the better resourced parts of the world, fetuses weighing 500 g or more or a gestational age above 24 weeks can survive although they may be handicapped. A missed miscariage is a nonviable intrauterine pregnancy that has been retained within the uterus without spontaneous abortion. Aim is to compare the synergistic effect of methotrexate versus letrozole before misoprostol for induction of first trimester missed miscarriage. Method: The study was conducted at Minia University Hospital and Eledwa General Hospital in the period from February 2021 to February 2022. The study included 199 women randomly allocated into two groups: Group (A): 99 women received letrozole (2.5 mg×3 tablets/day) + misoprostol (200 μg)/8h for 3 days], and Group (B): 100 women received [methotrexate (50 mg) im+ misoprostol (200 μg)/8h for 3 days]. Result: Both letroazole and methotrexate are effective in increasing the efficiency of misoprostol in inducing first trimester missed with a better side effects profile in the letrozole group. Conclusion: Letrozole administration prior to misorostol can be a safe and effective treatment in inducing first trimester missed miscarriage.