The human androgen receptor (AR) gene contains a CAG (glutamine) repeat polymorphism in exon 1 that is inversely associated with transcriptional activity of the AR. We studied the association of AR CAG repeat length, fat-free mass (FFM), and testosterone in two independent cohorts: 294 Caucasian men, aged 55-93 yr, from the Study of Osteoporotic Risk in Men (STORM), and 202 Caucasian volunteers (112 men and 90 women), aged 19-90 yr, from the Baltimore Longitudinal Study of Aging (BLSA). Subjects were genotyped to determine the number of AR CAG repeats and grouped as carrying either < 22 or > or =22 repeats. Whole body soft tissue composition was measured by dual-energy X-ray absorptiometry. Men with greater CAG repeat number exhibited significantly greater total FFM than those with fewer CAG repeats in both cohorts (STORM: 59.2 +/- 0.3 vs. 58.0 +/- 0.4 kg, P = 0.02; BLSA: 57.2 +/- 1.1 vs. 53.8 +/- 1.1 kg, P = 0.04). Similar results were observed for total FFM normalized to height. No differences were seen in women in the BLSA cohort. In the BLSA cohort, serum testosterone levels were higher in subjects with greater repeat number (P = 0.003). This same pattern approached significance in the STORM cohort (P = 0.07). In conclusion, the androgen receptor CAG repeat polymorphism is associated with FFM in men in two independent cohorts. Additional studies are needed to confirm this observation and to clarify the mechanisms involved.