To determine guidelines for biopsy in men with normal prostate-specific antigen (PSA) levels and suspected prostate cancer. The clinical-sonographic features of 91 lesions of reduced echogenicity in 83 men with normal PSA levels who underwent transrectal ultrasound-guided biopsy were analyzed. Sixteen men (19%) had cancer, two with bilateral foci, and four had prostatic intraepithelial neoplasia (PIN). Fourteen of 47 discrete hypoechoic lesions yielded cancer or PIN versus only five of 44 ill-defined vaguely hypoechoic lesions (P = .03). Fifteen of 18 malignant lesions exceeded 1 cm in longest dimension. In 47 men, sonographic and digital rectal examination (DRE) findings corresponded; 17 (36%) had cancer or PIN. By contrast, of 36 patients with differing sonographic and DRE findings, only three (8%) had malignancy at biopsy (P < .01). Predictors of malignancy at sonography of the peripheral prostate gland in men with normal PSA levels include (a) lesion size, (b) degree and focality of hypoechogenicity, and (c) correspondence with the site of DRE abnormality.