Tumor necrosis factor-alpha (TNF-alpha) is a potent catabolic factor to skeletal muscle. Single-nucleotide polymorphisms (SNPs) in the promoter region of the TNF-alpha coding gene, TNF, have been implicated in the interindividual variation in TNF-alpha production via transcriptional regulation. The present study investigated the association of muscle phenotypes with five TNF promoter SNPs, which potentially have biological significance. Female and male volunteers (n = 1,050) from the Baltimore Longitudinal Study of Aging were genotyped, and their regional and total body muscle mass, and arm and leg muscle strength were measured. Results indicated that putative high-expression alleles at positions -1031 and -863, individually or in combination in the haplotype 1031C-863A-857C-308G-238G, were associated with lower muscle mass in men. Specifically, carriers of -1031C, compared with noncarriers, exhibited lower arm muscle mass (6.4 +/- 0.1 vs. 6.8 +/- 0.1 kg, P = 0.01) and appendicular skeletal muscle mass (ASM) (24.3 +/- 0.4 vs. 25.4 +/- 0.2 kg, P = 0.02), with leg muscle mass and the ASM index (ASMI; kg/m(2)) also tending to be lower (P = 0.06 and 0.07). Similarly, -863A allele carriers (linked with -1031), compared with noncarriers, exhibited lower arm muscle mass (6.4 +/- 0.1 vs. 6.8 +/- 0.1 kg, P = 0.04). Carriers of the haplotype 1031C-863A-857C-308G-238G, compared with noncarriers, exhibited lower arm muscle mass (6.3 +/- 0.2 vs. 6.8 +/- 0.1 kg, P < 0.01), trunk muscle mass (25.7 +/- 0.5 vs. 26.9 +/- 0.3 kg, P < 0.05), and ASM (24.1 +/- 0.5 vs. 25.3 +/- 0.2 kg, P < 0.025), with tendencies for lower leg muscle mass and ASMI (P = 0.07 and 0.08). Results indicate that genetic variation in the TNF locus may contribute to the interindividual variation in muscle phenotypes in men.