We report a woman with unilateral Adie's pupil associated with peripheral sensorimotor polyneuropathy, elevated anti-Hu antibody, and primary mediastinal small cell carcinoma (SCC). To our knowledge, this is the first report of Adie's pupil in a patient with mediastinal SCC. Although rare, Adie's pupil and sensorimotor polyneuropathy may be the first manifestation of cancer. Its rapid recognition facilitates an early diagnosis and treatment.