To expand the clinical use of botulinum toxin A (BTX-A) in treating patients with small prostates and symptomatic benign prostatic hyperplasia (BPH). BTX-A injection into the prostate in patients with voiding dysfunction and large prostates has been reported. Sixteen men with symptomatic BPH, a prostate volume less than 30 cm3, peak flow rate less than 12 mL/s, and with refractory disease after at least 1 month of alpha-blocker treatment received BTX-A 100 U injection into the prostate transperineally under transrectal ultrasound guidance. The clinical effects were evaluated at baseline and after treatment. No significant local or systemic side effects were observed in any of the patients. All patients reported subjective improvement starting at approximately 1 week and achieved a maximal effect after 1 month that was maintained at 3 and 6 months. At 6 to 12 months (mean 10) of follow-up, no patient had symptom recurrence. The mean prostate volume, symptom score, and quality-of-life index were significantly reduced by 13.3% (from 19.6 +/- 1.2 to 17.0 +/- 1.1 cm3), 52.6% (from 18.8 +/- 1.6 to 8.9 +/- 1.9), and 44.7% (from 3.8 +/- 0.3 to 2.1 +/- 0.3), respectively. The maximal flow rate increased significantly by 39.8% (from 7.3 +/- 0.7 to 11.8 +/- 0.8 mL/s). In 2 patients who underwent biopsy 1 month after BTX-A injection, terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick end labeling staining demonstrated an increase in apoptotic activity, not only in the glandular component, but also in the stromal component of the prostatic tissue. BTX-A injected into the prostate is a promising treatment for patients with small prostates and symptomatic BPH.