Infectious mononucleosis, caused by primary Epstein-Barr virus (EBV) infection, is usually a benign, self-limited lymphoproliferative disorder. We report a case of a 21-year-old woman who presented with fever, sore throat, severe neutropenia, and absolute lymphocytosis with atypical lymphocytes. In situ hybridization for EBV-encoded small RNA performed on the marrow aspirate clot specimen demonstrated scattered positive cells. EBV serology was compatible with primary infection. Flow cytometry immunophenotypic studies performed on aspirate material revealed a profoundly expanded population of CD8+ T-cell receptor (TCR)-alphabeta T cells with uniform expression of CD94. No evidence of a monoclonal T-cell population was found as assessed by V(beta) use with flow cytometry and by TCR gamma-chain gene rearrangement using a polymerase chain reaction method. Uniform expression of CD94 in an exuberant reactive proliferation of CD8+ TCR-alphabeta T cells in infectious mononucleosis has not been reported previously, and combined with atypical morphology might be misinterpreted as a malignant neoplasm.