The purpose of this study is to clarify the concept and differential diagnosis among neurasthenia, chronic fatigue syndrome (CFS) and depression by observing the treatment and course of three cases. Some suggestions for further research, aimed at improving the treatment, will be offered in this paper. Case 1: A 48-year-old female primary school teacher was referred to our psychosomatic outpatient clinic with excessive fatigue and sleep disturbance for the past 6 months. Although she suspected herself to have CFS from the Internet information, our diagnosis was probable CFS. On the basis of her symptoms of headache, concentration impairment, dizziness, auditory hypersensitivity, irritability and inability to relax, she was diagnosed as neurasthenia by ICD-10 criteria. She was treated with Maprotiline and Alprazolam and graded exercise therapy (GET) for 3 months and returned to work. During the following year she still complained of easy fatigability. Case 2: A 32-year-old unemployed female was referred with back and abdominal pain, general malaise, insomnia and menstruation irregularity for more than one year. She thought she had CFS, but somatoform disorder was provisionally considered on the basis of objective findings. During the treatment with SSRIs, however, delusions of persecution and reference became obvious. She became well soon after her drug treatment was changed to Perospirone with a change of diagnosis. This case showed to us that sufficient attention is necessary not to mistake delusion for CFS. Case 3: A 25-year-old female office worker was referred with multi-joint pain, easy tiredness of 8 months' duration and irritability and inability to work for 6 months. She was suffering from cervical lymph nodes tenderness, multi-joint pain, sore throat and post-exertion malaise which were emerged before depressive episodes, and was diagnosed as CFS. She improved in health with GET, cognitive behavioral therapy and administration of Paroxetine. She found a new job one year later. Neurasthenia and CFS are often considered to be the cultural variance of the same illness in different countries. The diagnostic label of neurasthenia was also used in some countries to avoid the stigma associated with mental disorders. Considering the present condition and history which may imply diagnostic abuse of neurasthenia, we think it useful to the welfare of patient and family to make a positive diagnosis of CFS instead of an ambiguous diagnosis of neurasthenia. This therapeutic approach will contribute greatly to the elucidation of the brain function of fatigue.