Changes in lymphocyte surface markers during Epstein-Barr virus (EBV) associated infectious mononucleosis (IM) were re-examined because (1) these changes may provide information about host immune restraints to the initiation of a malignant process and (2) problems in the identification of B lymphocytes were often not appreciated in previous observations. An acute and transient reduction of IgM- and IgD-bearing B lymphocytes in the peripheral blood of these patients was demonstrated. The numbers of cells bearing Fc receptors and T lymphocytes were less consistently altered. It is hypothesized that the reduction of IgM- and IgD-bearing cells is caused by interference with the production of these cells or alternately their elimination by the virus or activated T lymphocytes.