Clear cell cribriform hyperplasia (CCCH) of the prostate is an unusual form of benign prostatic hyperplasia characterized by a nodular proliferation of clear cells with small, uniform nuclei. The authors studied 15 cases of CCCH by immunohistochemistry and 13 of them by DNA flow cytometry to establish the immunohistochemical and DNA profile of this lesion. Patients ranged in age from 58 to 88 years (mean, 68 years). Follow-up of a mean of 22 months showed all patients alive with no evidence of malignant prostatic disease. All 13 CCCHs showed diploid DNA content; in contrast, among 4 papillary/cribriform carcinomas of the prostate used for comparison, 3 were aneuploid and 1 was diploid. A basal cell layer was demonstrated in all 15 CCCHs by the use of the 34 beta E12 anti-high-molecular-weight keratin antibody (EAB-903) that reacts with the basal cells but not with the acinar cells of the prostate. A continuous basal cell layer was not evident in the carcinomas. The blandness of the epithelium, the well-defined nodular configuration, the presence of a basal cell layer demonstrable by immunocytochemistry, and the lack of aneuploidy as determined by DNA flow cytometry together lend support to the concept that CCCH is a benign lesion.