BACKGROUND: Prostate basal cell lesions can have architectural and cytologic atypia that mimic prostate adenocarcinoma. Immunohistochemical stains for basal cell markers are most helpful in the differential diagnosis. All of the published studies show basal cell lesions are positive for basal cell keratins, whereas adenocarcinoma is negative for both. We reported two cases of prostate basal cell lesions with negative basal cell keratin expression by immunohistochemistry. STUDY DESIGN: We reported the histologic and immunohistochemical profiles of two cases of basal cell lesions of the prostate. RESULTS: Histologically, both cases were highly suspicious for prostate adenocarcinoma with infiltrative growth pattern and significant nuclear atypia. The atypical glands in both cases were negative for basal cell keratins. However, both lesions were positive for another basal cell marker, p63, confirming that they were basal cells in origin, rather than prostate adenocarcinoma. CONCLUSION: Prostate basal cell lesions can occasionally be negative for basal cell keratins by immunohistochemistry and therefore may be misdiagnosed as prostate adenocarcinoma. We recommend using both p63 and basal cell keratins simultaneously in the workup of atypical prostate lesions to avoid such a misdiagnosis. © Science Printers and Publishers, Inc.