To determine the psychiatric morbidity of patients complaining of chronic fatigue, we undertook a prospective evaluation of 100 adults (65 women and 35 men; mean age, 41 years; and mean duration of chronic fatigue, 13 years). The study was conducted in an internal medicine outpatient clinic. In addition to a comprehensive medical evaluation, the patients were administered the 260-item Diagnostic Interview Schedule, a highly structured instrument that enabled the physician-interviewer to make accurate psychiatric diagnoses. A thorough follow-up examination was given an average of 8.4 months later. Sixty-six patients had one or more psychiatric disorders that were considered a major cause of their chronic fatigue (mood disorder, 47 patients; somatization disorder, 15 patients; and anxiety disorder, nine patients). Five patients had medical conditions that were considered a major cause of their fatigue. The complaint of chronic fatigue remained unexplained in 31 patients. In this prospective study, two thirds of cases of chronic fatigue appeared to be caused by psychiatric disorders. A thorough evaluation of the mental health of patients complaining of chronic fatigue could therefore provide pharmacologic and psychotherapeutic approaches and avoid unnecessary and costly medical investigations and therapies.