Plantar warts continue to represent a therapeutic challenge due to treatment resistance and high recurrence rates. Intralesional methotrexate, a cytotoxic chemotherapeutic agent with in-vitro anti-viral properties has been used for many dermatological indications. Two previous studies evaluated intralesional injection of diluted methotrexate (in 0.5, 1, and 2 mg/ml dilutions) in the treatment of warts and found it poorly effective.The concentrations used in these studies were much lower than those used for other indications. The current, open-label, prospective, pilot study aimed to evaluate the safety and efficacy of the intralesional injection of full concentration (25 mg/ml) methotrexate in the treatment of plantar warts. Twenty patients with plantar warts, 10 (50%) males, and 10 (50%) females, with mean ± SD age of 28.45 ± 8.66 years (range, 18-46 years) received biweekly sessions of intralesional methotrexate (25 mg/ml) until complete clearance or for a maximum of 6 sessions. Complete clearance of warts was achieved in 2 (10%), 6 (30%), and 7 (35%) patients after 4, 5, and 6 sessions, respectively. Another 8 (40%) patients showed partial improvement after 6 sessions. The response rate did not correlate significantly with the number of warts. Nine (45%) patients did not report any side effects. Pain and bruises were reported by 8 (40%) and 6 (30%) patients, respectively. These findings suggest that biweekly sessions of full (25 mg/ml) concentration of methotrexate are a safe and effective treatment for plantar warts. It may be considered an alternative line of treatment for resistant cases.