Background: Prior to a first-trimester abortion, a vaginal misoprostol administration has been shown to have less adverse effects than either an oral or sublingual dose. Objective: The aim of the current work was to determine whether a combined therapy with isosorbide mononitrate and misoprostol for preoperative cervical ripening in the first trimester would result in improved clinical effectiveness and fewer side effects compared with misoprostol used alone. Patients and methods: This randomized clinical trial study included a total of 54 women with first trimester missed abortion between 7-12 weeks, attending at Gynecologic Oncology Unit, Department of Obstetrics and Gynecology, Faculty of Medicine, Zagazig University Hospitals. They were divided into two equal groups: Group I: included 27 cases received 400 µg misoprostol inserted in the posterior fornix 4 hours prior to the surgical evacuation. Group II: included 27 cases received 20 mg isosorbide mononitrate and 200 µg misoprostol inserted in the posterior fornix 4 hours prior to the surgical evacuation. Results: Both groups were effective in achieving cervical ripening in terms of effacement, dilatation and softening but combination group was more effective than misoprostol group. The operative duration was statistically significantly shorter in combination group than in misoprostol group. Colicky lower abdominal pain was statistically significant and more prominent in group I (Misoprostol group) while headache was more significant in group II. Conclusion: It could be concluded that combination of both misoprostol and NO donors makes a synergism in action with fewer side effects. It softens the cervix and decreases its length with less operative time. It has less abdominal pain than misoprostol alone