Objectives To evaluate the side effects, tolerability, and efficacy of transurethral microwave thermotherapy with urethral cooling (cooled TUMT) for chronic prostatitis/chronic pelvic pain syndrome in a prospective feasibility trial. Cooled TUMT, using the Targis system from Urologix, is an established treatment option for benign prostatic hyperplasia (BPH) with minimal side effects. Methods Patients with intractable chronic prostatitis/chronic pelvic pain syndrome and symptoms for more than 3 of the 6 months before treatment (National Institutes of Health-Chronic Prostatitis Symptom Index [NIH-CPSI] pain score of at least 8) were randomized to cooled TUMT at an intraprostatic temperature of either ∼55°C or ∼70°C. Tolerability, side effects, and efficacy were measured with standard diagnostic tests, including the NIH-CPSI. Subgroup analysis was performed to evaluate the effects with and without BPH comorbidity. Results A total of 42 patients were included in the study; 39 patients successfully completed treatment and 35 completed follow-up through 12 months. The baseline versus 12-month mean NIH-CPSI score was total score 23.4 ± 6.4 versus 11.5 ± 10.2 (improvement in mean value of 51%), pain score 11.5 ± 2.8 versus 4.6 ± 4.9 (improvement in mean value of 60%), quality-of-life impact score 7.2 ± 2.9 versus 3.8 ± 3.8 (improvement in mean value of 47%; all P <0.0001), and urinary score 4.7 ± 2.8 versus 3.1 ± 3.0 (improvement in mean value of 34%; P = 0.0079). Treatment discomfort was within the ranges reported for patients with Targis-treated BPH. Two patients had reduced sperm motility. Side effects were minimal and transient, resolved spontaneously or with medication, and were similar regardless of treatment temperature or BPH comorbidity. Conclusions Cooled TUMT appears to be promising for intractable chronic prostatitis with or without BPH. Longer follow-up and a larger trial are required to evaluate the fertility impact and longer term durability further.