We report the case of an 81-year-old patient with a pleomorphic giant cell adenocarcinoma of the prostate. After diagnosis, he rapidly developed bone metastasis and died within 1 year. This variant of acinar adenocarcinoma is extremely rare and prognosis is poor. This entity has been included into the 2016 WHO classification. The principal differential diagnosis is urothelial carcinoma. To assess the prostatic origin, routine immunohistochemistry can be problematic. Loss of epitopes in this poorly differentiated entity can occur, such as loss of expression of PSA and p504s. We recently described a very sensitive and specific marker of prostate cancer, HOXB13, which once again has proven to be highly specific and sensitive. This is the first description of a pleomorphic giant cell prostate cancer expressing HOXB13.