Nineteen patients with heterophil-positive infectious mononucleosis were followed with serial blood sampling for an average of 14.6 mo. A preillness serum sample, obtained more than 2 mo before onset of illness, was available from 9 patients. A total of 141 samples were tested under identical conditions for total IgE levels by a paper-disc radioimmunoassay. Hematologic and serologic studies were also done. IgE changes showed a definite pattern, consisting of an elevation early in illness, rapidly followed by a significant drop reaching a nadir by the third month, then gradually returning to the preillness level (PIL) over a period of about a year. On the average, the peak was about 3 times the PIL, and the nadir about half the PIL. The IgE peak always coincided with the peak of atypical lymphocytes, and in no instance did it occur later than the peaks of other hematologic or serologic changes. No definite relationship was noted between IgE levels and the severity of illness. Heterophil-positive infectious mononucleosis is the first well-defined infectious disease found to be associated with such a pattern of IgE response.