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Extramammary Paget's disease (EMPD) is a rare cutaneous adenocarcinoma generally arising in the anogenital region. Surgery is still considered the treatment of choice for patients with EMPD, while Radiotherapy is a common alternative for inoperable cases and it's necessary in case of lack of surgical radicality. In this article, we described our experience and a review of the literature, with a particular focus on radiation-induced toxicity and on the feasibility of re-irradiation. A 70-year-old patient with EPMD underwent adjuvant radiotherapy in 2015. After 28 months for recurrence another radiant treatment was performed. No G3 (CTCAE v4) toxicity were recorded. In the last follow-up visit at 18 months, no signs of relapse were reported. A search strategy of the bibliographic database PubMed was performed. The inclusion criteria for the articles were case report, clinical prospective, or retrospective studies with histological confirmation of EMPD of scrotum and penis; studies with patients undergoing RT; studies in the past 30 years. In most of the 14 reported studies, RT was overall well tolerated. The major observed toxicity was G3 skin toxicity in one study. To our knowledge, there are no other cases of EPMD re-irradiation in literature. Our patient showed an excellent response and tolerated very well the high doses of both the radiation treatments. This suggests that the tolerance of skin to re-irradiation following a long period between the two treatments may be comparable to the normal constraints.