The purpose of this study is to determine the effectiveness of three-dimensional conformal radiotherapy delivered to the fossa of the prostate and seminal vesicles as salvage treatment for a prostate-specific antigen (PSA) level that becomes undetectable and subsequently begins to rise postprostatectomy. Between August 1994 and December 1997, 14 patients with prostate cancer whose PSA became undetectable after a radical prostatectomy subsequently developed a rising PSA, had no evidence of metastatic disease, and were treated with three-dimensional conformal radiotherapy at the University of California, Davis Cancer Center. Gleason scores ranged from 4 to 9 (29% of the patients had a Gleason score > or =8). The seminal vesicles were involved in three (21%) cases and the surgical margins were involved in seven (50%) cases. PSA values ranged from 0.3 to 6.7 (median: 0.7) ng/ml at the start of radiotherapy. Daily 1.8-2.0-Gy fractions were administered to total doses at isocenter ranging from 60.6 to 74.2 (median: 64.9) Gy. None of the patients received hormonal therapy. Follow-up ranged from 13 to 36 (median: 22) months. For patients with a preradiotherapy Hybritech PSA < or = 1.0 ng/ml, the Kaplan-Meier estimate of the 2-year biochemical disease-free survival rate is 67%, whereas for patients with a preradiotherapy PSA more than 1.0 ng/ml, the 2-year biochemical disease-free survival rate is 20% (p = 0.17). Because of the small number of patients, the difference is not statistically significant. A positive microscopic margin had no impact on the results obtained with salvage radiotherapy. Only one of four patients with a poorly differentiated adenocarcinoma remains free of disease. Acute toxicity was mild and did not require medication (Radiation Therapy Oncology Group grade I): four (29%) patients experienced genitourinary morbidity and three (21%) patients experienced gastrointestinal morbidity. With regard to late toxicity, one (7%) patient developed a urethral stricture requiring dilatation (Radiation Therapy Oncology Group grade III). All five patients who were potent at the start of radiotherapy remain potent. Medicare's median reimbursement for salvage three-dimensional conformal radiotherapy in this study ($7,512 in 1999 U.S. dollars) is equivalent to its reimbursement for a 17-month course of goserelin hormonal therapy. Patients with prostate cancer who develop an undetectable followed by a rising PSA postprostatectomy should be referred for salvage treatment with radiotherapy when their PSA is still less than or equal to 1.0 ng/ml. Salvage three-dimensional conformal radiotherapy is well tolerated and is less expensive than more than 17 months of goserelin.