<p>Warts are a common dermatological problem caused by human papillomavirus (HPV). There are various therapeutic techniques for warts, including chemical, physical, destructive, anti-proliferative and immunotherapy. Ionic contra-viral therapy (ICVT) (furosemide and digoxin) is a novel therapeutic approach for the treatment of warts. Methotrexate (MTX) is a chemotherapeutic agent with cytotoxic properties commonly prescribed in dermatology. This clinical study aimed to assess and compare the efficacy and safety of intralesional ICVT (digoxin and furosemide) versus intralesional methotrexate in the treatment of plantar warts. This comparative study included forty patients with multiple plantar warts who were classified into 2 groups: Group I (20 patients) treated with intralesional ICVT and group II (20 patients) treated with intralesional methotrexate, weekly till improvement or for a maximum of 5 sessions. Clinical and dermoscopic evaluation at base line, each session and monthly for 3 months after last session. Group I showed a statistically significant reduction of number and size of warts, (70%) of patients showed complete clearance compared with only (10%) in group II. Regarding dermoscopic findings, in group I there was a highly statistically significant reduction of dotted, linear blood vessels, pink or red background and well or ill-defined margin of warts before and after treatment. Additionally, there was a statistically significant reduction of yellow or grey background and smooth surface scales. However, group I has more frequent side effects with 70% reporting pain, (15%) reporting burning sensation and 5% having erythema compared with (20%) only in group II complaining of pain. In Conclusion Intralesional injection of ICVT (digoxin and furosemide) was effective and superior to intralesional methotrexate in treatment of planter wart.</p>