Background: Warts are tumors or growths caused by infection with Human Papilloma virus (HPV). Currently, over 170 HPV types have been identified. They are common presenting disease in children and adolescents which spread by direct contact or autoinoculation. Objective: The present work aimed to study the efficacy and safety of intralesional injection of methotrexate (MTX) for treatment of plantar warts and its possibility to be an alternative for the ordinary treatment. Patients and methods: sixty Egyptian patients presented with plantar warts were enrolled into our study. The patients were recruited from the Dermatology Outpatient Clinic of Al-Azhar University Hospital in the period from January 2019 to June 2019. Patients were classified into; control group (30 patients) that were Injected by normal saline and study group (30 patients) that were injected by MTX. Results: In intralesional MTX group, 2 patients (6.7%) showed complete improvement, 8 patients (26.7%) showed partial improvement and 20 patients (66.7%) showed no improvement. In intralesional saline group, 3 patients (10%) showed complete improvement, 4 patients (13.3%) showed partial improvement and 23 patients (76.7) showed no improvement. Conclusion: In this study, there was no statistically significant difference between the therapeutic responses to intralesional MTX injection and saline. Intralesional MTX injection was safe but less effective. No serious side effects were reported. Reported adverse events were local reactions in the form of swelling, pain and infection