The association of urothelial carcinoma with osteoclast-like giant cells is an exceptionally rare event. To our knowledge, there are no published reports of the cytopathologic characteristics of osteoclast-rich undifferentiated carcinoma of the urinary tract. We report herein, the case of a 63-year-old man who was evaluated at The Johns Hopkins Hospital for gross hematuria of 4 months duration. Urinary cytology displayed high-grade malignant cells with scattered osteoclast-like giant cells in a background of acute inflammation and abundant red blood cells. Subsequently, a transurethral tumor resection was performed, which revealed infiltrating undifferentiated carcinoma with osteoclast-like giant cells. The rarity of this neoplasm and its resemblance to other giant cell-rich processes may pose diagnostic difficulties. A review of the important differential diagnoses is also presented.