Detection of persistent or recurrent prostate cancer by digital rectal examination (DRE) after definitive radiotherapy is difficult. With the availability of transrectal ultrasonography (TRUS), the detection of prostate cancer has improved substantially. Since 1987 we have used TRUS to evaluate the prostate after definitive radiotherapy. A hypoechoic lesion suggestive of cancer was identified in 45 of 56 patients (80%) studied. Sonographically directed transrectal needle biopsies were performed in 27 of these (60%), and 16 (59%) were positive for cancer. The presence of a palpable nodule suggestive of cancer (present in 7 patients) was not predictive of a positive biopsy specimen. In 14 patients ultrasound-guided and digitally-guided biopsies were performed at the same time; 8 (57%) of the ultrasound-guided biopsy specimens were positive compared with only 4 (29%) of the digitally-guided biopsy specimens. In all 7 patients with an elevated serum level of prostate-specific antigen (PSA) an ultrasound-guided biopsy result was positive. Random biopsies of sonographically normal (isoechoic) areas of the prostate were performed in 8 patients, but only 2 specimens (25%) were positive for cancer. Ultrasound-guided transrectal biopsy of hypoechoic lesions was a safe and effective technique for identifying residual cancer in the irradiated prostate, regardless of the palpable findings. In the presence of an elevated PSA level, such biopsies invariably identified residual cancer. The use of TRUS, ultrasound-guided biopsy, and the measurement of PSA, in addition to DRE, may aid in the detection of residual cancer after definitive radiotherapy.