Prostate needle biopsies occasionally contain an atypical small acinar proliferation (ASAP) that is suspicious for, but not diagnostic of, adenocarcinoma. The histologic features and clinical significance of this finding are unexplored. We evaluated 33 cases of ASAP with at least one follow-up needle biopsy seen at Mayo Clinic from 1993 to 1996. Numerous histologic and clinical features were assessed to determine their predictive value for adenocarcinoma on subsequent biopsy. Mean patient age was 61.6 years (range 45-72). Adenocarcinoma was identified on follow-up biopsy in 15 of 33 patients (45%), with a median follow-up of 9 months (range 1-27). Gleason score varied from 4 to 7 (mean 5.9). Two patients (6%) had subsequent diagnoses of ASAP after one and three repeat biopsies. Digital rectal examination, serum prostate-specific antigen, and a variety of histologic findings were not predictive of cancer on follow-up biopsy. These histologic findings included number of biopsy cores (mean 5.5), number of acini per focus of ASAP (mean 7.9), number of foci (mean one), variation in acinar size, nuclear enlargement (none, 12% of cases; mild, 45%; moderate, 33%; severe, 10%), nucleolar enlargement (none, 27%; mild, 46%; moderate, 27%), luminal mucin (39%), crystalloids (6%), focal chronic inflammation (64%), adjacent atrophy (100%), and adjacent high-grade prostatic intraepithelial neoplasia (PIN) (42%). Stratification of suspicion in cases of ASAP without PIN into three categories ("favor benign, uncertain, and favor carcinoma") was somewhat predictive of subsequent cancer (20%, 25%, and 60% of cases with subsequent cancer, respectively), but the results were not significant. The high predictive value of ASAP for subsequent adenocarcinoma warrants repeat biopsy. No single clinical or pathologic feature appeared to increase the likelihood of subsequent cancer.