Histological separation of synovial sarcomas from malignant peripheral nerve sheath tumors can be difficult and available immunohistochemical markers sometimes give rise to overlapping staining patterns. Additional markers are needed to better define the two entities in the routine surgical pathology practice. To this end, we explored diagnostic applications of HMGA (HMGA1 and HMGA2) protein immunohistochemistry in comparable groups of synovial sarcoma and malignant peripheral nerve sheath tumors. The histological diagnosis of these cases was confirmed by the presence or absence of synovial sarcoma specific SYT-SSX fusion transcript analyzed by real-time reverse transcription polymerase chain reaction. In all, 13 malignant peripheral nerve sheath tumors and 15 synovial sarcomas were included in this study. Immunohistochemically, most malignant peripheral nerve sheath tumors expressed both HMGA1 and HMGA2 protein (12/13 and 12/13 cases, respectively) with moderate to strong nuclear staining patterns. Most cases of synovial sarcomas demonstrated variable expression of HMGA1. However, significant immunoreactivity for HMGA2 was present in the glandular component of a biphasic tumor (1/1) and rarely detected in monophasic synovial sarcomas (1/14). In summary, expression of HMGA2 is a feature of MPNST but not of synovial sarcoma and immunohistochemical staining of HMGA2 may be a useful marker to separate malignant peripheral nerve sheath tumor from synovial sarcoma.