One of the major diagnostic challenges in prostate needle biopsy interpretation is definitive establishment of a malignant diagnosis based on a minimal or limited amount of carcinoma in needle biopsy tissue. Major and minor diagnostic criteria should be used for interpretation of small foci of carcinoma. The constellation of findings and a combination of the major and minor diagnostic criteria permit a definitive diagnosis of focal adenocarcinoma. The differential diagnosis of minimal prostatic adenocarcinoma in needle biopsy tissue is broad and includes many benign lesions. The benign entities most likely to be misdiagnosed as minimal prostatic adenocarcinoma are atypical adenomatous hyperplasia (adenosis) and atrophy. High-grade prostatic intraepithelial neoplasia and a descriptive diagnosis of focal glandular atypia or atypical small acinar proliferation also should be considered before diagnosing minimal adenocarcinoma. The most valuable adjunctive study for the diagnosis of minimal adenocarcinoma is immunohistochemistry using antibody 34betaE12, reactive against basal cell–specific high-molecular-weight cytokeratins. Most cases can be diagnosed based on H&E-stained sections without this immunostain. Most minimal carcinomas in prostate needle biopsy tissue are of intermediate histologic grade, and most are indicative of pathologically significant carcinoma in the whole prostate gland.