Osteoporosis, a multifactorial common disease, is believed to result from the interplay of multiple environmental and genetic factors that regulate bone mineral density (BMD). Tumor necrosis factor receptor associated factor-interacting protein (I-TRAF) is an essential effecter of the tumor necrosis factor receptor-signaling cascade, one of the most potent bone-resorbing systems. In genetic studies of 382 Japanese adult women, we found that genotypes of two promoter variations of I-TRAF gene, -1542T/G and -525G/C, were similarly associated with radial BMD levels. Two variations were in almost complete linkage disequilibrium (D' = 0.978, r 2 = 0.917, χ 2 = 695, 2, P = 3.4 x 10 - 1 5 3 ), and there were two exclusive haplotypes (-1542T/-525C, frequency 0.74, and -1542G/-525G, frequency 0.24) among our test subjects. When BMD values were compared among the three haplotypic categories (-1542G/-525G homozygotes, heterozygotes, and -1542T/-525C homozygotes), BMD was lowest among -1542G/-525C homozygotes (mean +/- SD = 0.382 +/- 0.060 g/cm 2 ), highest among -1542T/-525G homozygotes (0.405 +/- 0.051 g/cm 2 ), and intermediate among heterozygotes (0.395 +/- 0.056 g/cm 2 ) (r = 0.11, P = 0.030). The observed trend supported a codominant effect of the relevant haplotype of I-TRAF gene in determination of radial BMD. These results suggested that variation of I-TRAF might be an important determinant for postmenopausal osteoporosis.