Several case reports and retrospective studies have demonstrated that intralesional methotrexate (MTX) could be a very effective and safe alternative treatment of keratoacanthoma (KA). Here, we report a rapid clinical efficacy of two intralesional MTX injections (total dose 40 mg) that were performed 1 week apart in the treatment of a large KA lesion of the dorsal hand in a 99-year-old woman. The lesion, with a 3-cm major axis diameter and a thickness of 2 cm with a central ulceration had rapidly appeared on the right dorsal hand. A 3-mm punch biopsy confirmed the diagnosis of a well-differentiated KA-type spinous cellular carcinoma. Due to the presence of comorbidities (arterial hypertension and atrial fibrillation) and chronic treatment with antihypertensive and oral anticoagulant drugs, treatment with intralesional MTX was proposed to the patient. Two intralesional MTX injections of 20 mg each were performed 1 week apart. A very fast resolution of the lesion was observed after the first injection. A week after the second injection a full resolution of the skin lesion was observed, with a nearly complete resolution of the central ulceration. The treatment was very well tolerated. No local or systemic side effects were observed. This case report confirms that intralesional MTX could be considered an effective and safe treatment of KA also in very old subjects.