Testosterone was administered transdermally to hypogonadal men under three protocols. In the first protocol, it was shown that peak levels of testosterone were achieved three to eight hours after scrotal application of a transdermal therapeutic system containing 5, 10, or 15 mg of testosterone, and values at 22 hours were greater than 60% of peak values. In the second protocol, patients were treated with 10-mg systems for four weeks followed by 15-mg systems for eight weeks. Serum samples were obtained three to five hours after application of the transdermal therapeutic system. Testosterone increased from a pretreatment level (mean +/- SE) of 1.5 +/- 0.4 nmol/L to 15.2 +/- 3.4 nmol/L at four weeks, 18.6 +/- 3.3 nmol/L at eight weeks, and 17.3 +/- 2.8 nmol/L at 12 weeks. The serum testosterone/dihydrotestosterone (DHT) ratio fell from 4.53 to 2.47 at four weeks and was similar at eight and 12 weeks, reflecting a greater rise in DHT with this route of treatment (normal testosterone/DHT ratio, 9/1 to 12/1). Eight patients were treated with the 15-mg systems for an additional year. Seven of the eight were compliant and maintained serum testosterone levels (at six time points from two to 12 months [mean +/- SE] ) ranging from 11.5 +/- 1.2 to 44.9 +/- 2.4 nmol/L. It was possible to achieve physiological serum levels of testosterone by transdermal administration of testosterone in two thirds of our hypogonadal men.