Tenosynovial giant cell tumors arise from synovium of joints, bursae, or tendon sheaths, and are classified into localized and diffuse types based on the growth pattern and clinical behavior. The mononuclear component of these tumors includes small histiocytoid cells and large mononuclear cells, which are positive for desmin in about 50% of cases. This study seeks to further characterize the immunophenotype of these tumors, and investigates the utility of clusterin as a diagnostic marker. Immunostaining for clusterin was performed on 40 cases of tenosynovial giant cell tumor (11 localized and 29 diffuse). Most cases were also stained for desmin, CD163, CD21, and CD35. Four cases were stained for podoplanin/D2-40 and CXCL13. Clusterin staining was diffuse and strong in the large mononuclear cells in all cases. Desmin positivity in the large cells was identified in 24 out of 34 cases (71%), but was seen in only a subset of cells (<5% to 80%), with 19 out of 24 cases (79%) showing positivity in 10% or less. The large cells were positive for podoplanin in 4 out of 4 cases, but negative for CD163, CD21, CD35, and CXCL13. The smaller histiocytoid cells were positive for CD163 and negative for all other markers. When present, non-neoplastic synoviocytes were positive for clusterin and podoplanin, and focally positive for desmin. Clusterin is a highly sensitive marker for tenosynovial giant cell tumors, which has diagnostic utility in challenging cases. The observed staining patterns provide evidence linking the large mononuclear cells with normal synoviocytes and support that tenosynovial giant cell tumors are neoplasms showing synovial differentiation.