The DNA content and proliferative indexes of seven cases of tenosynovial giant cell tumor of tendon sheath, diffuse type (TGCT-D); 11 cases of tenosynovial giant cell tumor of tendon sheath, localized type (TGCT-L); and seven cases of pigmented villonodular synovitis (PVNS) were analyzed by flow cytometry in an attempt to assess objectively their biologic differences. Three cases of TGCT-D manifested an aneuploid DNA content and four had a diploid DNA pattern. All cases of TGCT-L and PVNS showed a diploid DNA content. The proliferative indexes for TGCT-D were significantly higher than those found in the other two groups. There was no histopathologic feature that correlated with the aneuploid DNA pattern found in two of the three cases of TGCT-D. Only one of the three aneuploid DNA content TGCT-D cases displayed marked cellular pleomorphism with dense fibrous stroma; in that case there was recurrence 4 years after initial excision. Our data further support that TGCT-D, TGCT-L, and PVNS are histopathologically similar but clinically distinct lesions. The high proliferative indexes of TGCT-D may reflect a rapid, uncontrolled growth that may explain its aggressive biologic behavior. The presence of an aneuploid DNA pattern in some cases of TGCT-D in this study, coupled with the reported chromosomal abnormalities and occurrence of malignant transformation in these lesions, clearly supports their neoplastic nature.