Giant cell tumor of tendon sheath (GCTTS) is a common soft tissue lesion and presents as a firm, slow-growing, non-tender mass adjacent to the tendon sheath. It can be further classified into diffuse or localized types based on its growth pattern. Using cytomorphologic analysis, we assessed the feasibility of fine-needle aspiration (FNA) as an initial diagnostic modality for GCTTS. Forty-one cases of image-guided FNA of GCTTS were retrospectively retrieved from the archives of The Johns Hopkins Hospital. Clinical information, imaging studies, histopathology, and other ancillary studies were also reviewed. The majority of the cytology specimens demonstrated hypercellularity. A uniform population of spindled to polygonal stromal cells constituted more than half of the cellularity. Other cell types frequently present included multinucleated giant cells, hemosiderin-laden macrophages, and foamy histiocytes. Nuclear grooves or intranuclear pseudo-inclusions present in stromal cells were also distinctive cytomorphologic features, but only present in less than a quarter of the cases. Our study has shown the usefulness and accuracy of imaging-guided FNA as a diagnostic tool for GCTTS. Diagnostic accuracy can be optimized with a thorough review of clinical history, careful physical examination, and radiologic correlation. Diagn. Cytopathol. 2012; © 2012 Wiley Periodicals, Inc.