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Aim: To evaluate and compare the efficacy of methotrexate injection in management of persistent simple ovarian cyst versus the use of transvaginal ultrasound aspiration alone. Patients and Methods: This randomized controlled study was conducted at Tanta University Hospitals in the period from April 1, 2016 to October 31, 2016. Patients were randomly allocated into two groups; each group has 25 patients with benign persistent simple ovarian cyst. Group I: Patients were subjected to transvaginal aspiration of the cyst. Group II: patients were subjected to methotrexate injection inside the cyst. Patients in both group were followed up at 1, 3, 6 months after procedure for the recurrence and occurrence spontaneous pregnancy. Results: The mean age in group I was 28.8 years, and the mean age in group II was 26.52 years with non-significant difference. Also there was non-significant difference between both groups regarding size of the cyst. No case recorded to have a cyst recurrence in group II and four cases in group I within six months with significant difference (P value 0.037), and there was non-significant differences as regard the pregnancy rate and complications. Conclusion: Transvaginal intra-cystic methotrexate injection is a safe and effective choice for management of persistent simple benign ovarian cyst.