The treatment of residual prostate cancer after irradiation is often associated with significant morbidity and a high failure rate. Percutaneous transperineal interstitial microwave thermoablation is a minimally invasive procedure used experimentally in our institution to treat selected patients with failures of external-beam radiation therapy for prostate cancer. The aim is to ablate all residual intraprostatic cancer thermally. Patients were treated under general or epidural anesthesia with transrectal ultrasound guidance of transperineal placement of the microwave antennas. The rectum, urethra, and a developed space between the prostate and surrounding tissues were actively cooled. The minimal target temperature of the prostate was 65 degrees C for 15 min. The temperature was measured in all cases with interstitial prostatic thermosensors and in selected cases with online magnetic resonance scanning. Thirty-seven patients with apparently localized prostate cancer after failure of treatment for cure with external-beam therapy were subjected to this treatment, and 20 of these patients have at least 12 months of follow-up. The initial prostate specific antigen (PSA) concentration ranged from 0.2 to 120 ng/mL. At 12 months, 12 of 20 patients had no biochemical or histologic evidence of disease, and 11 of 14 patients with initial PSA concentration <10 ng/mL had no evidence of disease. Five of the thirty-seven patients were treated with 3 months of neoadjuvant androgen ablation because the volume of their prostates precluded adequate heating. The average volume decline was 28%, which allowed all men to be treated. Two of these patients have been followed for at lease 1 year, and neither shows evidence of recurrence. Side effects of treatment in all patients were modest. Preliminary results suggest that this treatment might be useful in selected patients as a salvage therapy after failure of radiation therapy for localized prostate cancer.