In 1997, approximately 1 million 18-gauge prostate needle core biopsies were performed in the United States. Yet limited data exist on the effect of histologic sampling on detection of carcinoma in needle biopsy tissue, and no data have been published on the diagnostic yield of complete histopathologic examination of prostate needle biopsy specimens. We sought to evaluate the diagnostic effect of obtaining additional sections after a nonmalignant diagnosis was given on three initial slides. This prospective study was of 200 consecutively identified cases. Complete histologic examination of all needle biopsy tissue from 100 cases diagnosed as atypia (encompassing high-grade prostatic intraepithelial neoplasia [PIN] and focal glandular atypia) on the initial three slides was compared with complete examination for a control population of 100 cases diagnosed as benign prostatic tissue on the initial three slides. New histologic abnormalities in levels were characterized as to diagnostic category, distribution in additional slides and morphometrically determined size. Complete histologic sampling of prostate needle biopsy specimens with serial sections entirely through the paraffin block required a mean of 30 slides per block, with a mean of 4 sections per slide. In 17 (17%) cases with atypia diagnosed on the initial three slides, a new histologic abnormality was detected in levels. In 4 (10%) of 40 cases of focal glandular atypia, definitive carcinoma was present on additional sections, including the first additional slide. In no case with a diagnosis of benign prostatic tissue (n = 100) or high-grade PIN (n = 60) on the three initial slides was carcinoma diagnosed on additional slides. Additional histologic sampling after a diagnosis of isolated high-grade PIN does not seem necessary; these patients with high-grade PIN should undergo rebiopsy. Because of the profound consequences of a definitive diagnosis of prostatic carcinoma, we recommend obtaining a single additional slide with several 3-microm sections after a diagnosis of focal glandular atypia has been given for three initial slides of needle biopsy specimens from the prostate.