Pigmented villonodular synovitis is an uncommon benign lesion that is characterized by diffuse synovial proliferation. Based on animal models, this lesion has been conjectured previously to be reactive in nature. In this report, the authors present the histologic and cytogenetic findings for a pigmented villonodular synovitis that was excised from the right knee of a 47-year-old man. Trisomy 7 was observed in 24 of 75 (35%) metaphases obtained from short-term culture of cells from this tumor. These findings suggest that some cases of pigmented villonodular synovitis represent clonal, neoplastic proliferations.