Numerous studies have claimed that CDX2 is relatively specific and sensitive in establishing a gastrointestinal origin in metastatic tumors of unknown origin. We have recently seen 2 cases of prostatic adenocarcinoma (PCa) on needle biopsies with diffuse strong nuclear staining for CDX2 sent for consultation. One case was a prostatic duct adenocarcinoma in a man with a prostate-specific antigen (PSA) value of 327 ng/mL, and the other was a PCa with a Gleason score (GS) of 4 + 4 = 8 in a man with a PSA value of 15 ng/mL. An adenocarcinoma with GS 3 + 3 = 6 from the contralateral side did not express CDX2. Because documented examples of this phenomenon are rare, we investigated the immunoexpression of CDX2, using tissue microarrays (TMAs). Three slides of TMAs were used to stain 708 tissue samples (0.6 mm in diameter) containing either benign or malignant prostate tissue, as well as control tissues from various anatomical sites including colon. In total, 195 samples of primary PCa with GS of 6 (n = 41), 7 (n = 21), and 8 (n = 8); 195 samples of benign prostate tissue; and 185 samples of metastatic PCa were studied. Of 70 radical prostatectomy specimens examined for PCa in TMAs, 4 (5.7%) were positive for CDX2, showing Gleason score of 6 (n = 3) and Gleason score of 7 (n = 1). Focal moderate positive staining was seen in benign prostate tissue in 7 (11.7%) of 60 radical prostatectomy specimens. None of the metastatic PCa expressed CDX2. CDX2 may uncommonly be focally expressed in benign prostatic glands. Staining in PCa is less common and appears independent of GS and is usually patchy and focal and of lesser intensity than in colonic tissue. However, rarely strong and diffuse staining may be seen. Positive CDX2 staining in high-grade prostate cancer (ductal, cribriform, and solid) may be confused with secondary carcinoma of colonic origin. Routine histopathology, positive PSA immunostaining, and clinical findings can help confirm the correct diagnosis.