We report a case of a 64-year-old man with POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) syndrome that had been previously misdiagnosed as systemic sclerosis. He had typical symptoms of POEMS syndrome, however, the existence of skin sclerosis, contracture of fingers and pigmentation were similar to that of systemic sclerosis. Ten patients, including the patient discussed in this case, visited our department between 1990 and 2011. Among them, five patients had skin sclerosis. Therefore, we compared skin lesions and clinical/laboratory features of POEMS syndrome and systemic sclerosis in an attempt to distinguish these disorders. Regarding the cutaneous and laboratory findings, the existence of hemangioma or hypertrichosis is indicative of POEMS syndrome. By contrast, the existence of systemic sclerosis-specific autoantibodies, nail fold bleeding, digital ulcer/digital pitting scar or telangiectasia is highly suggestive of systemic sclerosis. To our knowledge, this is the first report to discuss in detail the differentiation between POEMS syndrome and systemic sclerosis.