A case of superficially invasive cutaneous squamous cell carcinoma (SCC) of the sole containing numerous mucin-producing vacuolated cells resembling “signet-ring” cells is reported. The 2 cellular components of the tumor, both squamous and mucinous, were atypical with pleomorphic nuclei, and expressed the same immunophenotype, consistent in weak and focal positivity for cytokeratin 5/6 and epithelial membrane antigen (EMA) and weak cytoplasmic and nuclear positivity for p16. Real-time PCR genotyping demonstrated the presence of high-risk human papillomavirus (HPV) type 18. We diagnose our case as “cutaneous SCC with mucinous metaplasia” and discuss the differential diagnoses with other skin tumors exhibiting mucin-containing cells, in particular with adenosquamous carcinoma and mucoepidermoid carcinoma. Although HPV 18 is not uncommon in cervico-vaginal pathology, where is often associated with mucinous adenocarcinoma or adenosquamous carcinoma of the cervix, its detection has been rarely reported in cutaneous SCC. In our case, the association of mucinous metaplasia and oncogenic high-risk HPV 18 in a cutaneous SCC may be of interest to the dermatopathologist. Further observations need to confirm whether the histopathologic finding of mucinous metaplasia in an atypical squamous cell proliferation could be a clue for investigating the presence of oncogenic high-risk HPV infection, with particular regard to HPV 18 subtype.