To determine the effect of prostatic irradiation on the production of prostate specific antigen (PSA), serum PSA levels were measured in 36 men who received pelvic irradiation (45 to 65 Gy.) for nonprostatic malignancies, and compared with those of a control group of 79 men of comparable age without prostate cancer or prior pelvic irradiation identified from the records of the Massachusetts General Hospital internal physicians. The median PSA level was lower in the irradiated group than in the control group (0.65 versus 1.1 ng./ml.). Of the irradiated patients 47% had undetectable PSA levels versus 20% of the controls (p = 0.004, Fisher's exact test). A group of 27 prostate cancer patients who received up to 68 Gy. 8 to 16 years (median 10 years) previously and who remained clinically disease-free were also studied. The median PSA level was less than 0.5 ng./ml. The proportion of patients with undetectable PSA levels was significantly higher than that of the controls (p < 0.001) but it was not significantly different from those irradiated for other pelvic cancers. Of those patients 67% had an undetectable PSA level and 78% had a level of less than 1 ng./ml. Our study suggests that radiation therapy results in a permanent decrease in PSA production by the prostate gland and that patients whose PSA values do not reach less than 1 ng./ml. following radical radiation therapy for prostate cancer are unlikely to be long-term clinical disease-free survivors.