Tumor-associated glycoprotein 72 is a high-molecular-weight sialomucin that is expressed selectively in various adenocarcinomas, including those of the prostate. We utilized the monoclonal antibodies B72.3 and CC49 to examine the expression of TAG-72 in high-grade prostatic intraepithelial neoplasia (PIN), localized adenocarcinomas (pathologic stages B and C), as well as matching primary and nodal lesions from patients with stage D adenocarcinomas. Immunoreactivity within PIN lesions was detected within 20 (87%) and 17 (74%) of 23 specimens immunostained with B72.3 and CC49, respectively. Benign epithelium and stromal tissue did not immunostain with either antibody at the concentrations tested. Immunostaining was detected within the malignant cells in 30 (77%) and 35 (90%) of 39 localized adenocarcinomas using B72.3 and CC49, respectively. Immunostaining was localized to the cytoplasm and cellular membranes of the malignant cells and within the lumen of malignant glands. Seven of 17 (41%) primary lesions from patients with stage D adenocarcinomas demonstrated immunoreactivity when stained with B72.3. Immunoreactivity was detected in 8 of 10 (80%) of these tissues immunostained with CC49. Within nodal lesions obtained from these patients, immunostaining was observed in 3 of 17 (18%) and 6 of 10 (60%) of the specimens immunostained with B72.3 and CC49, respectively. We used a semiquantitative technique to compare the extent of immunoreactivity among well-differentiated (Gleason score < 6), moderately differentiated (Gleason 6-7), and poorly differentiated (Gleason score > 7) tumors. We observed an inverse correlation of TAG-72 expression to Gleason scores. Furthermore, TAG-72 expression was reduced in the matching primary and metastatic lesions of stage D adenocarcinomas as compared to localized lesions. These findings demonstrate a phenotypic relationship of PIN to invasive adenocarcinomas and support the concept that PIN is a preinvasive neoplastic lesion. Furthermore, expression of TAG-72 may represent an early event in the neoplastic transformation of the prostatic epithelium. The data demonstrate a diminution in TAG-72 expression in poorly differentiated and advanced-stage prostatic adenocarcinomas.