Lambert-Eaton myasthenic syndrome (LEMS) is a neuromuscular disorder characterized by defective neurotransmitter release at presynaptic terminals. It is caused by an IgG autoantibody reacting against voltage-gated calcium channels. Severe LEMS complicated by ventilatory failure is rare. We report a case of small-cell lung cancer (SCLC) presenting with LEMS and ventilatory failure in a 67-year-old man who initially presented with progressive limb weakness for 6 months and tachypnea with shallow breathing for 1 week. LEMS was diagnosed through electrophysiologic studies. Chest radiography and computerized tomography showed a huge mass lesion over the left anterior and middle mediastinum with an encasement of the left pulmonary artery. Cytologic examination of ultrasound-guided fine needle aspiration disclosed SCLC. Successful treatment in combination with plasma exchange and chemotherapy resulted in dramatic tumor regression and LEMS remission, which were confirmed by chest radiography and electrophysiologic studies. This case suggests that plasma exchange and chemotherapy can be effective in treating SCLC with severe LEMS that produces ventilatory failure.