PURPOSE: Genetic variation in myostatin, a negative regulator of skeletal muscle, in cattle has shown remarkable influence on skeletal muscle resulting in a double-muscled phenotype in certain breeds; however, DNA sequence variation within this gene in humans has not been consistently associated with skeletal muscle mass or strength. Follistatin and Activin RIIB (ACVR2B) are two myostatin-related genes involved in the regulation/signaling of myostatin. We sought to identify associations between genetic variation and haplotype structure in both follistatin and ACVR2B with skeletal muscle related phenotypes. METHODS: Three hundred and fifteen males and 278 females aged 19-90 years from the Baltimore Longitudinal Study of Aging were genotyped to determine respective haplotype groupings based on HapMap data. Whole-body soft tissue composition was measured by dual-energy X-ray absorptiometry. Quadriceps peak torque (strength) was measured using an isokinetic dynamometer. RESULTS: Women carriers of ACVR2B haplotype group 1 exhibited significantly less quadriceps muscle strength (shortening phase) than women homozygous for haplotype group 2 (109.2 ± 1.9 vs 118.6 ± 4.1 N·m, 30°/sec, respectively, p = 0.036). No significant association was observed in men. Male carriers of follistatin haplotype group 3 exhibited significantly less total leg FFM than non-carriers (16.6 ± 0.3 vs 17.5 ± 0.2 kg, respectively, p = 0.012). No significant associations between these haplotype groups were observed in women. CONCLUSION: These results indicate that haplotype structure at the ACVR2B and follistatin loci may contribute to inter-individual variation in skeletal muscle mass and strength, though these data indicate sex-specific relationships.