Several lines of evidence suggest that apoptosis dysregulation plays an important role in cancer metastasis. In this study, to explore the possibility that the mutations of death receptors are involved in the metastasis mechanism, we analyzed the death domains of Fas and tumor necrosis factor-related apoptosis-inducing ligand-receptor 1 and -2 (TRAIL-R1 and -R2) genes for the detection of somatic mutations in 57 breast cancers with (n = 34) or without (n = 23) metastasis to the regional lymph nodes. We found seven mutations (three TRAIL-R1 and four TRAIL-R2 mutations), and these mutations were detected only in the breast cancers with metastasis. Furthermore, we also analyzed the allelic losses of chromosome 8p21–22, where TRAIL-R1 and R2 reside in the same series of breast cancers, and found that the allelic losses were significantly higher in metastatic breast cancers. We expressed the tumor-derived TRAIL-R1 and TRAIL-R2 mutants in 293 cells and found that apoptosis was suppressed. These data suggest that TRAIL-R1 and R2 genes are relevant to the frequent loss of chromosome 8p21–22 in breast cancer and that the inactivating mutations of TRAIL-R1 and -R2 genes play a role in the metastasis of breast cancer.