During a 6-year period, 53 patients with advanced tumors of the genitourinary tract were treated in Phase I protocols with deep regional hyperthermia in combination with irradiation (83%) or in combination with chemotherapy (11%). Primary tumors included those of bladder in 22 patients (41%), prostate in 20 patients (37%), kidney in 9 patients (17%), and ureter testicle or adrenal in 3 patients (5%). The majority (77%) had prior definitive therapy and had experienced treatment failure, and 11% had clinically important distant metastases. Treatment consisted of deep regional hyperthermia (mean of 4 sessions). In addition, 44 patients (83%) received irradiation (mean dose 39.2 Gy). The 1- and 3-year actuarial survival was 60% and 56%, respectively. Patients with carcinoma of the prostate had a 1- and 3-year survival of 82%. Complete response was observed in 7 patients (13%), partial response in 8 (15%), and nominal response in 13 (25%). Complete and partial response correlated well with histology of the tumor (adenocarcinoma), radiation dose (greater than 50 Gy), primary site (prostate, kidney), and treatment (hyperthermia-radiotherapy combination), (p = 0.02). There was no such correlation between response and thermal dose (p = 0.13). The treatment tolerance was good in 79% of patients. Treatment toxicity was limited to acute side effects, including pain during hyperthermia (47%), tachycardia greater than 140/min (7%), and blister formation in the treated area (4%). Phase II studies in previously untreated patients with locally advanced tumors of bladder, prostate, and kidney are needed for evaluation of the role of deep regional hyperthermia in the management of these cancers.