As compared to most cancers, MCC is particularly linked to immune suppression. Indeed, 7.8% of MCC patients are profoundly immune suppressed, with a 16-fold over-representation of MCC compared with the normal incidence. Notably, the impact of immune surveillance on the course of MCC is much more pronounced than on that of melanoma: while the ratio of melanoma to MCC is 60:1 in the normal population, it is 6:1 in the immune suppressed population. Moreover, there are more than 20 reported cases of complete spontaneous regressions of confirmed MCCs, which suggest the ability of the immune system to exert a sudden immune recognition and clearance of this tumor. Notably, regressions may also be induced by cessation of immune suppression. Another line of evidence for the immunogenicity of MCC is the observation, that a strong inflammatory infiltrate, particularly CD8+ T cells, within the tumor is associated with a favorable prognosis. The immunogenicity of MCC can be explained by the recently recognized viral pathogenesis of this tumor entity. Indeed, preliminary data from our MCC research network suggest that immune dominant T-cell epitopes derived from the oncogenic virus elicit spontaneous immune responses in MCC patients. Consequently, immune modulating strategies are particularly attractive for the therapy of MCC and may improve the disease-free survival as well as the overall survival of MCC patients if given in an adjuvant setting.