Background: Paget’s disease of the nipple is generally associated with an underlying invasive cancer or an underlying ductal carcinoma in situ. Epidermotropic theory maintains that Paget’s cells are derived from an underlying mammary in situ adenocarcinoma. Because p16 protein plays a major role in cell-cycle control and in tumoral cell mobility, we analyzed p16 expression in Paget’s disease of the nipple and in associated underlying ductal carcinoma in situ. Methods: The expression of p16 protein was analyzed by immunohistochemistry in eight cases of Paget’s disease of the nipple with associated underlying ductal carcinoma in situ. The Student’s t-test (2-tailed) was used to establish the equality of means. Results: The expression of p16 protein was observed in 87.5% (7/8 cases) both in the nipple disease and in the associated underlying ductal carcinoma in situ. The difference between the two populations was not statistically significant. In normal breast tissue, no expression of the protein was observed. Conclusion: The positive p16 expression in Paget’s disease of the nipple and the underlined ductal carcinoma in situ and its role in cell motility lead us to propose a role of p16 in the spread of this disease.