We have observed a group of typically younger patients with multiple foci of small, nonlobular, crowded, but relatively bland acini on needle biopsy and in prostatectomy specimens. It is unclear whether this architectural pattern, which we have termed diffuse adenosis of the peripheral zone (DAPZ), is simply a crowded glandular variant of normal prostate morphology or whether it represents a risk factor for the development of prostatic carcinoma. We studied 60 cases of DAPZ on needle biopsy in our consult practice from 2001 to 2007. Cases, on average, showed 72% of cores involved by DAPZ. Average patient age was 49 years (range: 34 to 73) and the average prostate specific antigen (PSA) level at the time of biopsy was 5.2 ng/mL (n=42). Forty-three (72%) men had available clinical follow-up with 35 (81%) patients undergoing rebiopsy and 8 (19%) followed with serial PSA measurements. Patients who were rebiopsied after DAPZ diagnosis had higher PSA levels than those who were followed by PSA levels alone (6.2 vs. 3.1 ng/mL, P=0.04). Of the rebiopsied cases, 20 (57%) were subsequently diagnosed with carcinoma, with an average of 15 months elapsed between initial biopsy and carcinoma diagnosis. Although the majority of tissue sampled in a typical DAPZ case had no cytologic atypia, in 65% of cases there were admixed rare foci of atypical glands with prominent nucleoli comprising <1% of submitted tissue. Patients with a subsequent diagnosis of carcinoma were more likely to have had DAPZ with focal atypia, although this did not reach statistical significance (70% vs. 36%, P=0.08). We histologically confirmed the carcinoma diagnosis in 18/20 cases. In 12/14 radical prostatectomies, we were able to review the slides. Eleven had Gleason score 3+3=6 adenocarcinoma in addition to background DAPZ; 9 showed peripheral zone organ-confined cancer, and 2 had focal extraprostatic extension. In one case of DAPZ misdiagnosed as cancer on biopsy, no carcinoma was found at prostatectomy. DAPZ is a newly described and diagnostically challenging mimicker of prostate cancer seen in prostate needle biopsies from typically younger patients. Our findings suggest that DAPZ should be considered a risk factor for prostate cancer and that patients with this finding should be followed closely and rebiopsied.