Immunoperoxidase strains for prostate-specific antigen (PSA), prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA), and cytokeratins (MAK 6 and CK-KES) were performed on 1 case of squamous cell carcinoma of the prostate and on 13 cases of squamous metaplasia of prostatic epithelium in an effort to demonstrate prostatic origin of the neoplastic and metaplastic cells and to differentiate them from primary or metastatic well-differentiated squamous cell carcinoma. The authors found no specific staining of the metaplastic or neoplastic cells for PSA and only focal single cell PAcP positivity in three cases of squamous metaplasia. All cases showed strong staining of surrounding normal glandular epithelium for both antigens. In all but one case, both the metaplastic and glandular epithelium had positive results for MAK 6 and CK-KES. EMA was expressed strongly in ten cases, was weak or variable in two, and had negative results in two cases of squamous metaplasia. In only four cases did the glandular epithelium have positive results for EMA. The remaining cases showed no staining. PSA and PAcP marking, therefore, may not be useful for separating atypical squamous metaplasia from well-differentiated squamous cell carcinoma or even primary prostatic from metastatic squamous cell carcinoma. These findings suggest that although prostatic glandular epithelial cells retain their ability to express some prostate-associated antigens, this ability is greatly reduced, lost, or not developed in cells that undergo metaplasia into squamous cells or that develop into squamous cell carcinoma.