TLE1, a transcriptional repressor essential in hematopoiesis, neuronal differentiation and terminal epithelial differentiation, has recently been shown in a single tissue microarray study to be a highly sensitive and relatively specific marker of synovial sarcomas. Expression of TLE1 has not, however, been studied in standard sections of soft tissue and bone tumors. We investigated TLE1 expression in a large series of well-characterized mesenchymal tumors, to more fully characterize the range of TLE1 expression. Standard sections of 163 bone and soft tissue tumors were immunostained for TLE1 (sc-9121, 1:100; Santa Cruz Biochemicals) using the Dako Dual Envision+ detection system. Nuclear positivity was scored as negative (<5% of cell positive), 1+ (5-25% of cells positive), 2+ (25-50% of cells positive), and 3+ (>50% of cells positive). Overall, TLE1 was expressed by 18 of 20 (90%) of synovial sarcoma, with 16 cases (89%) showing 2-3+ positivity. However, TLE1 expression was also seen in 53 of 143 (37%) non-synovial sarcoma, with 36 such cases (25%) showing 2-3+ positivity. TLE1 expression was commonly seen in peripheral nerve sheath tumors, including 33% of neurofibromas, 100% of schwannomas, and 30% of malignant peripheral nerve sheath tumors. Among non-neoplastic tissues, nuclear TLE1 expression was variably present in basal keratinocytes, adipocytes, perineurial cells, endothelial cells and mesothelial cells. Our study confirms the excellent sensitivity of TLE1 for synovial sarcoma. However, TLE1 expression is by no means specific for synovial sarcoma, being present in a number of tumors, which enter its differential diagnosis, in particular tumors of peripheral nerve sheath origin. Heterogeneity of TLE1 expression likely explains the differences between the present standard section study and the earlier TMA study. TLE1 may be of value in the differential diagnosis of synovial sarcoma, but should be used only in the context of a panel of antibodies. Morphology, ancillary immunohistochemistry for traditional markers such as cytokeratins and CD34, and molecular confirmation of synovial sarcoma-associated fusion genes should remain the 'gold standards' for this diagnosis.