Background. Prostate-specific antigen (PSA) is secreted exclusively by prostatic epithelial cells, and its serum concentration is increased in men with prostatic disease, including cancer. We evaluated its usefulness in the detection and staging of prostate cancer. Methods. We measured serum PSA concentrations in 1653 healthy men 50 or more years old. Those with PSA values ≥4.0 μg per liter then underwent rectal examination and prostatic ultrasonography. Ultrasound-directed prostatic needle biopsies were performed in the men with abnormal findings on rectal examination, ultrasonography, or both. The results were compared with those in 300 consecutively studied men 50 or more years old who underwent ultrasound-directed biopsy because of symptoms or abnormal findings on rectal examination. Results. Serum PSA levels ranged from 4.0 to 9.9 μ9 per liter in 6.5 percent of the 1653 men (107). Nineteen of the 85 men in this group (22 percent) who had prostatic biopsies had prostate cancer. Serum PSA levels were 10.0 μg per liter or higher in 1.8 percent of the 1653 men (30). Eighteen of the 27 men in this group (67 percent) who had prostatic biopsies had cancer. If rectal examination alone had been used to screen the men who had biopsies, 12 of the 37 cancers (32 percent) would have been missed. If ultrasonography alone had been used to screen these men, 16 of the 37 cancers (43 percent) would have been missed. Serum PSA measurement had the lowest error rate of the tests, and PSA measurement plus rectal examination had the lowest error rate of the two-test combinations. Conclusions. The combination of measurement of the serum PSA concentration and rectal examination, with ultrasonography performed in patients with abnormal findings, provides a better method of detecting prostate cancer than rectal examination alone. (N Engl J Med 1991; 324:1156–61.).