A large proportion of T lymphocytes isolated from the peripheral blood of acute infectious mononucleosis (IM) patients rapidly die when cultured in vitro, with greater than 50% dying within 12-15 h of seeding and up to 80% dying within 24 h. The cells die by apoptosis, a morphologically distinct mode of cell death that occurs in circumstances where death is a regulated event such as in embryonic development and hormone-dependent atrophy. In contrast, the level of cell death remained low in cultures of lymphocytes from controls and in the T cell depleted subpopulation from acute IM patients, with less than 2% and 10% of the lymphocytes dying by apoptosis after 36 h in culture, respectively. The rapid death of acute IM T cells in vitro does not involve soluble factors (including the serum fraction) or T cell to T cell contact. It is suggested that this observation may necessitate a re-evaluation of IM T cell function in vitro.