Introduction: Misoprostol is a widely used prostaglandin to terminate pregnancy in the second trimester. The route of drug administration has a significant effect on the quality of treatment. Objectives: In this study, we aimed to compare efficacy and adverse effects of vaginal and intrauterine extraamniotic administration of misoprostol in second-trimester termination. Patients and Methods: In a randomized clinical trial, 112 women with an intrauterine fetal death between 13– 24 weeks of gestation attended Akbarabadi hospital were enrolled during 2018-2019. Patients were randomly divided into two groups. In group A, 200 µg misoprostol was diluted in 10ml of normal saline and administered extra-amniotic every 4 hours. Group B received vaginal tablets (200 µg in each) according to FIGO protocol. The primary outcomes were the time needed to expel gestational products and hemoglobin level changes. Results: In group A, conception product expulsion occurred within an average of 7.52 ± 0.29 hours, significantly faster than group B (12.02 ± 0.42 hours; P<0.05). In group A, the Hemoglobin level decreased after intervention (-1.23 ± 1.20 g/dL), and the changes were more prominent than group B (-0.15 ± 0.51 g/dL; P<0.05). Conclusion: For pregnancy termination, intrauterine extra-amniotic administration of misoprostol is a more effective method than the vaginal route in the second trimester. However, regarding further hemoglobin decrease in this method, its safety is still unclear and needs to be approved by further clinical trials with a larger sample size. Trial Registration: The trial protocol was approved by the Iranian Registry of Clinical Trial (identifier: IRCT20190606043830N1; https://en.irct.ir/trial/40184, ethical code: IR.IUMS.FMD.REC1396.941129004).