Background: Cervical ripening is an important factor in predicting successful labor induction. In an unfavorable cervix, ripening should be done before induction. In this study, the effect of misoprostol and that of misoprostol plus estradiol on cervical ripening were compared. Methods: This randomized, double-blinded study included a total of 190 pregnant women who were identified for pregnancy termination due to maternal or fetal cause at 37 weeks with Bishop score of less than 4. The patients were assessed between April 2015 to April 2016 in two university hospitals at northeast Iran (Omol-Banin Hospital and Emam Reza Hospital, Mashhad). The patients who met the inclusion criteria were randomly assigned to two groups: the intervention group (Group A), who received 25 micrograms of vaginal misoprostol plus 50 micrograms of estradiol, and the control group (Group B), who received 25 micrograms of vaginal misoprostol only. Misoprostol was administered at 4-hour intervals until cervical ripening (Bishop score ? 8) or upon initiation of active phase in both the groups. The maximum dosage of misoprostol was three doses, whereas estradiol was administered only once. Results: In this study, the main causes of pregnancy termination were ROM and post-term. There was no significant statistical difference in the Bishop score between the two groups (P = 0.13). In addition, no significant difference was observed in the duration of time for cervical ripening (Bishop ? 8) between the two groups (P = 0.7). The duration between drug administration to the initiation of active phase and also from active phase to delivery showed no significant differences between the two groups (P = 0.49 and 0.24, respectively). There was also no significant difference in the delivery route (operative vaginal delivery or Cesarean section) (P = 0.2 and P = 0.91, respectively). Conclusion: From this study, the use of misoprostol plus estradiol did not improve cervical ripening or decrease the induction time. Further studies are recommended to investigate complementary results.