Skeletal muscle plays a central role in the overall health of individuals across all ages, and skeletal muscle phenotypes are influenced by both genetic and environmental factors. Tumor necrosis factor alpha (TNF-α), a key player in the innate and adaptive immune responses, has long been recognized as a potent catabolic factor mediating muscle wasting in various pathological conditions. Overproduction of TNF-α has been implicated in the etiology of age-associated muscle loss (sarcopenia). Individual capacities to produce TNF-α vary widely, which is partially attributable to gene sequence variations. The TNF-α coding gene, TNF, is highly polymorphic and single nucleotide polymorphisms (SNPs) in the promoter region of TNF have been implicated for the transcriptional regulation of TNF-α production, and associated with numerous inflammatory and infectious diseases. The purpose of the present study was to investigate the association of muscle phenotypes, including sarcopenia, with 5 TNF promoter SNPs, which are potentially of biological significance. A total of 1050 volunteers participating in the Baltimore Longitudinal Study of Aging (352 and 407 white women and men, 127 and 107 black women and men, and 30 and 27 non-white and non-black women and men) were genotyped for 5 TNF SNPs, and their regional and total body soft tissue masses and muscle strengths of upper and lower limbs were measured. Results indicated that TNF promoter SNPs are associated with muscle phenotypes in the participants: putative high TNF-α-producing alleles at positions -1031 and -863, individually or in combination in haplotype '1031C-863A-857C-308G-238G', are associated with lower muscle mass in males. These results suggest that genetic variation in the TNF locus may contribute to the inter-individual variation in muscle phenotypes, and imply that TNF-α may have a potential role in regulating body composition even in healthy people.