Immunological memory is a key characteristic of specific immune responses. Persistence of increased levels of precursor T cells is antigen-independent and is often used as an indicator of T cell memory. This study documents that, depending on the chosen readout, cytotoxic T lymphocyte (CTL) memory against lymphocytic choriomeningitis virus (LCMV) appears long- or short-lived in the absence of persisting antigen. To study T cell memory in the absence of persisting antigen, either short-lived antigens were used for immunization or adoptive transfer methods were used to eliminate possibly persisting antigen. These experiments revealed that increased specific precursor frequencies and CTL-mediated protection against an i.v. infection with LCMV were long-lived. In contrast, CTL-mediated protection against a peripheral infection of the skin with LCMV, or of the ovary with recombinant vaccinia virus, was short-lived. These results show that maintenance of increased specific CTL precursor frequencies and central T cell memory in lymphoid tissue (where preexisting neutralizing antibodies usually provide protection anyway) is long-lived and antigen-independent. In contrast, in protection against peripheral viral infections, where the relative kinetics of virus growth and virus elimination by T cells are of key importance, T cell memory is short-lived in the absence of antigen. This indicates that peripheral T cell memory in antibody-inaccessible tissues is mediated by antigen-activated effector T cells and apparently not by specialized memory T cells.