Transrectal ultrasound (TRUS) guided multiple systematic random biopsies are presently the method of choice for determining the presence or absence of prostate cancer. TRUS image information is only used to guide the biopsy needle into the prostate, but not to localize and target cancerous lesions. Our aim in this study was to evaluated the possible predictive value of tumor suspicious endosonographic lesions of the prostate for prostate biopsies. We prospectively compared six systematic biopsies with lesion guided biopsies in a consecutive series of 217 patients. All patients had a prostate specific antigen (PSA) level of >4 ng/ml without a history of prostate disease. In a subgroup of 145 men with sonomorphologic lesions suggestive for prostate cancer (hypoechoic areas or asymmetries predominantly in the peripheral zone), lesion-guided biopsies were taken in addition to the systematic biopsies. We evaluated the number of tumors which were diagnosed or missed by both of the biopsy strategies. Of the 217 evaluated patients, 64 (29%) had histology confirmed cancer. Four patients with negative sextant biopsies had a positive TRUS guided biopsy. Out of 145 patients with a normal TRUS, three were cancer positive by sextant biopsy. A total of 1,387 individual biopsy cores were evaluated. Of the 1,304 systematic biopsy cores, 182 (14%) were positive and 1,122 (86%) negative. Of the 329 TRUS lesion guided biopsy cores 139 (42%) were positive and 190 (58%) negative. Patients with tumor suggestive TRUS lesions have a considerably higher risk of being diagnosed with prostate cancer compared to patients without such lesions. Both systematic sextant and TRUS lesion guided biopsies missed detectable prostate cancer in a minority of patients. Taking the endosonographic morphology of the prostate gland into consideration for biopsy strategies may improve the quality of the biopsy and avoid unnecessary invasive procedures in selected cases.