Respiratory failure due to polyneuropathy associated with POEMS syndrome (Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is unusual. In this report, we describe a 47-year-old male patient with polyneuropathy related to POEMS syndrome who suffered from hypercapnic respiratory failure due to progressive weakness of the respiratory muscles. His respiratory muscle strength significantly improved after plasma exchange and was extubated successfully. To our knowledge, this is the first case of POEMS syndrome with aggressive polyneuropathy that was successful treated by plasma exchange and our experience provides insight regarding the optimal management of such patients.