During a 2-year period, 23 patients (14 girls, 9 boys) with chronic fatigue were referred to the Pediatric Infectious Disease Clinic of a tertiary care center, representing 19% of all out-patients seen in that clinic during that time. The median age was 14 years and the median duration of symptoms before referral was 6 months; 65% had missed at least 2 weeks of school and 30% required a home tutor. There were few positive physical findings and no elevation of white blood cell count (median, 7000/mm3) or erythrocyte sedimentation rate (median, 5 mm/hour). Twenty-five percent had no evidence of Epstein-Barr virus infection, 15% had current or recent infection and 60% had past infection; 33% of the latter had detectable antibody to early antigen but the titers were low. Human herpesvirus 6 titers in 8 patients were similar to those in age- and sex-matched controls. Of 17 patients contacted after a median of 26 months, 76% reported definite improvement, although 38% of these still experienced occasional symptoms. In this referral population chronic fatigue was a common presenting complaint, was associated with marked degrees of dysfunction and bore no relationship to Epstein-Barr virus or human herpesvirus 6 infection. In most children the disorder was self-limited, although a minority were persistently or severely affected.