Previous studies in Ghana and the United States have shown that the great majority of primary Epstein-Barr virus (EBV) infections in infants remain silent and fail to evoke hematologic and heterophil antibody responses typical of infectious mononucleosis (IM). In the present study, a search was made for cases of IM among children less than age 49 mo and a diagnosis of this disease was made in 32 patients. The great majority had fever, tonsillar pharyngitis, prominent cervical lymphadenopathy, and respiratory symptoms. There were significant differences in serologic responses between the 11 infants and toddlers aged 10-24 mo and 21 young children aged 26-48 mo. In particular, heterophil antibody responses were detected in only 3 of 11 infants (27.3%) compared with 16 (76.2%) of 21 children. The infants also had less prominent viral capsid antigen (VCA) specific IgM antibody responses (63.6% versus 100%) and a lower frequency of peak IgG anti-VCA titers of ≥1:320 (45.4% versus 76.2%). In addition, only 45% of the infants showed antibody responses to early antigens that were directed against the restricted (R) component in 2 and against the diffuse (D) component in 3. In contrast, anti-D responses of the type seen in 80%-85% of young adults with IM were already present in 11 (52.4%) of the 21 children aged 26-48 mo. Peripheral blood smears from all patients showed numerous atypical lymphocytes and easily fulfilled standard hematologic criteria for IM. At the conclusion of this study, EBV antibody tests were performed on serum samples from 53 other sick patients of similar age whose blood smears lacked the minimal morphological criteria for IM. In only 4 cases (4/53, 7.5%) was there evidence for a recent or current primary EBV infection, thus validating the present morphological criteria as guidelines for determining which young children require EBV-specific serodiagnostic studies.