Although fatigue is one of the most common complaints in ambulatory care, research has been minimal. Of the 1159 consecutive patients surveyed in two adult primary-care clinics, 276 (24%) indicated that fatigue was a major problem. Fatigue was more prevalent in women than in men (28% vs 19%). Extensive clinical, laboratory, psychometric, and functional data were gathered for 102 fatigued patients and 26 controls. Laboratory testing was not useful in detecting unsuspected medical conditions or in determining the cause of fatigue. Depression or somatic anxiety or both were suggested by screening psychometric instruments in 82 fatigued patients (80%) compared with three controls (12%). Global dysfunction was marked, as reported by patients on the Sickness Impact Profile. The mean score on the Sickness Impact Profile of 11.3 for fatigued patients is similar to that reported for patients with major medical illnesses. After one year of follow-up, only 29 fatigued patients (28%) had improved. The high prevalence, persistence, and functional consequences of fatigue mandate a search for effective therapy.