Background. Testosterone increases lean mass and may help to counter the changes in muscle architecture associated with sarcopenia. This study was designed to investigate the effects of testosterone replacement therapy on skeletal muscle architecture in intermediate-frail and frail elderly men. Methods. A subgroup of 30 intermediate-frail and frail elderly men (65-89 years) with low to borderline-low testosterone levels were enrolled from a single-center randomized, double-blind placebo-controlled trial. Participants received either a transdermal testosterone (50 mg) or placebo gel daily for 6 months. Architecture (muscle thickness, fascicle length, and pennation angle) of the gastrocnemius medialis muscle was assessed by ultrasound imaging at baseline and after 6 months of treatment. Results. Serum testosterone increased from 11.6 +/- 3.5 to 18.0 +/- 8.1 nmol/L by 10 days after randomization in the active group (but not the placebo group) and was maintained throughout the treatment period. Testosterone treatment resulted in a preservation of muscle thickness at 6 months while it decreased in the placebo group (effect size 1.4 [95% confidence interval = 0.3-2.5; p=.015]). There was no significant effect of treatment on fascicle length (effect size 1.9 mm [95% confidence interval = -1.2 to 5.0 mm; p=.22]) or pennation angle (effect size 1.2 [95% confidence interval = -1.3 to 3.7; p=.32]). Conclusions. Testosterone replacement in intermediate-frail and frail elderly men is associated with preservation of muscle thickness. The results suggest that testosterone mitigates sarcopenia by improving muscle tissue to maintain a state of normality in aging men. ; 666PW Times Cited:5 Cited References Count:22