The role of prostate-specific antigen (PSA), a sensitive tumor marker for cancer of the prostate, has yet to be defined in patients treated with radiotherapy. To evaluate this, PSA and acid phosphatase (AP) were measured prospectively in 110 sequential patients who presented with locoregional carcinoma of the prostate and in whom radiotherapy was to be definitive treatment. Therapy was divided into the following treatment groups: external-beam radiotherapy alone (EBRT), EBRT with brachytherapy (EBRT + B), and hormone therapy either pre-EBRT or post-EBRT (EBRT + H). All patients have been followed for 1 to 17 months and a total of 521 posttreatment PSA determinations have been made. In 91 of 110 patients (83%) PSA was elevated pretreatment and correlated with clinical stage and subsequent relapse. There was no association with Gleason grade, assigned treatment group, or lymph node involvement. Acid phosphatase was elevated in only 31% of the patients initially and had no predictive value in subsequent failure. Nine patients have developed local and/or distant recurrence. None of the patients who failed had their PSA return to normal whereas 74 of 101 (73%) of the remainder have done so. Levels of PSA that do not return to normal during follow-up probably indicate active disease, often without evidence of clinical relapse. The authors conclude that PSA is a useful tumor marker for monitoring response to radiotherapy and may be a predictor of eventual failure thus identifying patients eligible for early intervention therapy as and when it becomes available.