Background and Purpose: Transurethral microwave thermotherapy (TUMT) is an effective therapy for symptomatic benign prostatic hyperplasia (BPH), but the trade-off between the magnitude of clinical improvement and side effects and patient tolerance has limited its appeal to patients and urologists. This study, using the TherMatrx TMx-2000, a TUMT device that directly heats the transition zone to greater than 50°C, has been focused on resolving these issues and developing a truly office-based therapy that is well tolerated with a benign post-treatment course. Patients and Methods: This study was multi-institutional and designed as a blinded, randomized, and sham-controlled trial. A series of 200 patients with an AUA Symptom Index (AUASI) of >12, a peak flow rate of <12 mL/sec, and cystoscopic evidence of BPH were randomized 2:1 (active to sham) and treated in seven physician offices under a Food and Drug Administration-supervised and audited premarket approval protocol. No intravenous sedation was used in any patient. Follow-up for the sham-treatment group was 3 months, at which time, patients could cross over to an active treatment. A total of 119 patients have completed 1-year follow-up. Results: The active and sham groups were statistically identical at baseline. The 1-hour total treatment was extremely well tolerated using urethral lidocaine and oral medications; not a single prostate block or parental dose of medication was required. The active-treatment group demonstrated a statistically significant reduction (p < 0.05) in AUASI at 3 months compared with sham treatment, with an AUASI decrease from 22.4 to 12.4 (n = 124) for active v 22.9 to 17 for sham (n = 62). For the 119 patients in the active arm who have reached 12 months, the AUASI has fallen to 10.6 points (47.1% decrease), and the peak flow rate has increased 5.0 mL/sec (58.1%). Postprocedure catheterization was typically 2 or 3 days, and the 16.8% of patients who failed their first voiding trial all voided within 1 week. No major adverse events such as stricture, rectal findings, or ejaculatory changes have been reported. Conclusions: This study demonstrates that the TherMatrx TMx-2000 TUMT effectively treats symptomatic BPH in the physician office with minimal morbidity.