OBJECTIVE The biology of tumors relapsing to bone is poorly understood. In this study, we initiated a search for genes that are implicated in tumors relapsing to bone in breast cancer. METHODS We analyzed 107 primary breast tumors in patients who were all lymph node negative at the time of diagnosis and all had experienced relapse. Total RNA isolated from frozen tumor samples was used to gather gene expression data using oligo microarrays. RESULTS A panel of 69 genes was found significantly differentially expressed between patients who experienced relapse to bone versus those who experienced relapse elsewhere in the body. The most differentially expressed gene, TFF1, was confirmed by quantitative reverse transcriptase polymerase chain reaction in an independent cohort (n = 122; P = .0015). Our differentially expressed genes, combined with a recently reported gene set relevant to tumors relapsing to bone in an animal model system, pointed to the involvement of the fibroblast growth factor receptor signaling pathway in preference of tumor cells that relapse to bone. Given that patients who experience relapse to bone may benefit from bisphosphonate therapy, we developed a classifier of 31 genes, which in an independent validation set correctly predicts all tumors relapsing to bone with a specificity of 50%. CONCLUSIONS Our study identifies a panel of genes relevant to bone metastasis in breast cancer. The subsequently developed classifier of tumors relapsing to bone could, after thorough confirmation on an extended number of independent samples, and in combination with our previously developed high-risk profile, provide a diagnostic tool for the recommendation of adjuvant bisphosphonate therapy in addition to endocrine therapy or chemotherapy.