The transdermal therapeutic system for testosterone (TTS-T) (ALZA Corp.), applied to the scrotal skin for twenty-two hours daily, was tested for twelve weeks on 4 men with hypogonadal impotence; 2 of these men wore TTS-T for as long as twenty-six months. The 40 cm2 system delivered a daily dose of 2.8 +/- 0.16 (S.E.) mg (nominal dose 2.4 mg) and the 60 cm2 system delivered a dose of 3.99 +/- 0.24 mg (nominal dose 3.6 mg). Both systems promptly increased serum testosterone and dihydrotestosterone (DHT) to physiologic levels, restoring normal erectile activity with an increased frequency of ejaculation and a positive effect on both mood and energy. There were no changes in serum sex binding globulin and estradiol, prostate or breast size, hematologic or liver function measures, or urinary flow and frequency. There were no significant changes in serum cholesterol or low-density lipoproteins, but high-density lipoproteins tended to decline slightly. There were no dermatologic problems associated with the system. The tenfold increase in DHT over baseline levels was attributed to 5-alpha reduction of testosterone in the scrotal skin. The TTS-T is convenient, reliable, and mimics normal physiologic testosterone secretion and levels more closely than conventional methods of testosterone replacement.