Objective: To characterize the clinical features and muscle pathology of paraneoplastic necrotizing myopathy. Background: Paraneoplastic syndromes involving many levels of the nervous system are well described, but there are only rare case reports of a necrotizing myopathy associated with cancer. Design: Case series. Results: We identified four patients with paraneoplastic necrotizing myopathy from muscle biopsies done at Washington University over a 10-year period. The patients (aged 38 to 76 years) presented with subacutely evolving, symmetric, proximal weakness. Tumor types included gastrointestinal adenocarcinoma (2 of 4), transitional cell carcinoma, prostatic carcinoma, and non-small cell lung carcinoma. Two patients died. Two others improved after treatment that included corticosteroids and tumor resection. Muscle pathology showed numerous necrotic fibers (8 to 100%) and intense alkaline phosphatase staining of the muscle connective tissue, but little inflammation. Conclusions: Paraneoplastic necrotizing myopathy is characterized by a rapidly progressive, symmetric, predominantly proximal weakness that produces severe disability. Muscle pathology demonstrates prominent necrosis with alkaline phosphatase staining of connective tissue and little inflammation. Evaluation for cancer is indicated in patients with these clinical and pathologic findings.