OBJECTIVE: To compare adolescents who do and do not recover from acute infectious mononucleosis in terms of fatigue severity and activity levels before, during, and in the 2 years following infection. DESIGN: Prospective case-control study. SETTING: The baseline and 12- and 24-month evaluations occurred in the subjects' homes. The 6-month outpatient visit occurred at Children's Memorial Hospital in Chicago, Illinois. PARTICIPANTS: Three hundred one adolescents (aged 12-18 years) with acute infectious mononucleosis. MAIN EXPOSURES: All participants were evaluated at baseline (during active infection). Six months following infection, 39 of them met criteria for chronic fatigue syndrome. These subjects were matched by sex and Tanner stage to 39 randomly selected screened-negative subjects. Both groups were reevaluated at 12- and 24-month follow-ups. OUTCOME MEASURES: Scores from the Fatigue Severity Scale and the Modifiable Activity Questionnaire. RESULTS: For both groups, physical activity levels declined and sleep increased as a result of having mononucleosis. Compared with their matched controls, adolescents with chronic fatigue syndrome reported significantly higher levels of fatigue at all points and spent significantly more time sleeping during the day 6 and 12 months following infection. The 2 groups did not differ significantly in terms of physical activity levels before, during, or after infection. There was a consistent trend for decreased physical activity in the chronic fatigue syndrome group. CONCLUSIONS: Adolescents with chronic fatigue syndrome appear to be pushing themselves in an attempt to maintain similar activity levels as their peers, but paying for it in terms of fatigue severity and an increased need for sleep, particularly during the day.