OBJECTIVE: This study assessed relationships among psychological symptoms, past and current psychiatric disorder, functional impairment, somatic symptoms, chronic fatigue, and chronic fatigue syndrome. METHOD: A prospective cohort study was followed by a nested case- control study. The subjects, aged 18-45 years, had been in primary care for either clinical viral infections or a range of other problems. Questionnaire measures of fatigue and psychological symptoms were completed by 1,985 subjects 6 months later; 214 subjects with chronic fatigue were then compared with 214 matched subjects without fatigue. Assessments were made with questionnaires, interviews, and medical records of fatigue, somatic symptoms, psychiatric disorder, and functional impairment. RESULTS: Subjects with chronic fatigue were at greater risk than those without chronic fatigue for current psychiatric disorder assessed by standardized interview (60% versus 19%) or by questionnaire (71% versus 31%). Chronic fatigue subjects were more likely to have received psychotropic medication or experienced psychiatric disorder in the past. There was a trend for previous psychiatric disorder to be associated with comorbid rather than noncomorbid chronic fatigue. Most subjects with chronic fatigue syndrome also had current psychiatric disorder when assessed by interview (75%) or questionnaire (78%). Both the prevalence and incidence of chronic fatigue syndrome were associated with measures of previous psychiatric disorder. The number of symptoms suggested as characteristics of chronic fatigue syndrome was closely related to the total number of somatic symptoms and to measures of psychiatric disorder. Only postexertion malaise, muscle weakness, and myalgia were significantly more likely to be observed in chronic fatigue syndrome than in chronic fatigue. CONCLUSIONS: Most subjects with chronic fatigue or chronic fatigue syndrome in primary care also meet criteria for a current psychiatric disorder. Both chronic fatigue and chronic fatigue syndrome are associated with previous psychiatric disorder, partly explained by high rates of current psychiatric disorder. The symptoms thought to represent a specific process in chronic fatigue syndrome may be related to the joint experience of somatic and psychological distress.