Twenty-one percent of 500 unselected patients, aged 17 to 50 years, seeking primary care for any reason were found to be suffering from a chronic fatigue syndrome consistent with "chronic active Epstein-Barr virus (EBV) infection." They had been experiencing "severe" fatigue, usually cyclic, for a median of 16 months (range, six to 458 months), associated with sore throat, myalgias, or headaches; 45% of the patients were periodically bedridden; and 25% to 73% reported recurrent cervical adenopathy, paresthesias, arthralgias, and difficulty in concentrating or sleeping. The patients had no recognized chronic "physical" illness and were not receiving psychiatric care. While antibody titers to several EBV-specific antigens were higher in patients than in age- and sex-matched control subjects, the differences generally were not statistically significant. A chronic fatigue syndrome consistent with the chronic active EBV infection syndrome was prevalent in our primary care practice. However, our data offer no evidence that EBV is causally related to the syndrome. Indeed, we feel that among unselected patients seen in a general medical practice currently available EBV serologic test results must be interpreted with great caution.