Surgical excision represents the primary treatment for malignant melanoma. On occasion, however, surgery may not be possible, and a different approach is required. Imiquimod is a Toll-like receptor 7 agonist involved in the activation of the innate immune system. We report the case of a 77-year-old female with a large, invasive, malignant melanoma of the malleolar area. Due to the size of the lesion, its location, and the patient's general condition, neither surgery nor radiotherapy were indicated. We offered topical treatment with 5% imiquimod to be applied once/day continuously over a 3-month period, pausing only when intense inflammation on the area of application occurred. Complete clinical and histological resolution of the lesion were observed. This case adds further merit to the growing body of evidence that imiquimod can be used to successfully treat malignant melanoma in cases where no other options are suitable.