Currently, pleomorphic rhabdomyosarcoma (RMS) in adults is considered to be extremely rare or nonexistent. The authors have identified 11 cases of pleomorphic RMS using the following criteria: pleomorphic sarcoma occurring within voluntary muscle, large polygonal or straplike cells with copious eosinophilic cytoplasm, desmin and myoglobin immunoreactivity, or ultrastructural evidence of sarcomeric differentiation. Ten patients were male, the median age at presentation was 56 years (range, 27-84), and the thigh (seven cases) was the most common site. Of eight cases with clinical follow-up, one patient is alive at 20 months, and seven died 2 to 28 months following diagnosis. The tumors were generally patternless, but several had storiform areas. Cross-striations were not identified. Immunostaining for muscle-related antigens was positive as follows: desmin (in 10 of 11 cases), myoglobin (in 10 of 11 cases), actin HHF-35 (in all 11 cases), smooth-muscle actin (in six of eight cases), sarcomeric actin (in six of nine cases), and fast myosin (in five of five cases). Staining for S-100 protein was negative in all cases. On electron microscopy (six cases), two tumors had well-differentiated rhabdomyoblasts with sarcomeres, Z-disks, and hexagonal arrays of myofilaments; three were poorly differentiated; and one contained immature mesenchymal cells only. Pleomorphic RMS can be distinguished from other pleomorphic sarcomas provided that well-fixed tumor tissue is available for immunohistochemical staining and electron microscopy. We consider that this distinction is important in view of the poor prognosis associated with pleomorphic RMS in this series