Background: Spiny keratoderma shows "music box spine" keratotic papules limited to the palms and soles and these lesions do not cause any trouble besides the cosmetic impairment and the sensation of roughness of hands and soles. Aim: To present cases and review the literature on spiny keratoderma. Patients/methods, results: Three cases of spiny keratoderma are presented. The first case is a 52-year-old man with protein S deficiency presented with multiple spiny keratotic papules on palms and soles for more than 30 years, referring to remove them with a razor blade. The second case is an 84-year-old man who was hospitalized due to a rectal adenocarcinoma diagnosed 2 months before and presented multiples papules on palms and soles that were present for more than 50 years, with worsening after being bedridden. The third case is a 59-year-old woman who had since birth together with relatives the same type of spiny keratotic papules on palms and soles. Conclusion: The authors discuss the epidemiologic data and differential diagnosis of spiny keratoderma, as well as the related literature. Associations with systemic disease or malignancy occur in some acquired cases. It is important to distinguish from other palmoplantar keratodermas as some of that can be linked to cutaneous and internal malignancies. To date, no cases of spiny keratoderma in patients with protein S deficiency and only one case of association with rectal carcinoma have been reported.