Palmoplantar keratoderma (PPK) refers to a genetically heterogeneous group of skin diseases, which may be inherited in autosomal dominant or recessive fashion. We observed a case of a 74-year-old man with Mal de Meleda, who developed malignant melanoma inside the hyperkeratotic palmar skin of the right hand. Many authors have reported a higher incidence of cancer in cases affected by palmoplantar hyperkeratosis both for hereditary association and particularly for mechanical damage of the affected areas. The association with melanoma has already been described, but not in a true Mal de Meleda type syndrome as in the case reported in this paper.