Cytotoxic T cell (CTL) memory was analyzed after infection with lymphocytic choriomeningitis virus (LCMV) and recombinant Listeria monocytogenes (rLM) expressing the complete nucleoprotein of LCMV (rLM-NP(actA)) or only the immunodominant epitope of H-2(d) mice (rLM-NP(118-126)). Immunization with LCMV and rLM induced a long-lived increased CTL precursor (CTLp) frequency specific for the viral (NP(118-126)) and for the bacterial (LLO(91-99)) epitope, respectively. However, after infection with rLM memory, CTLs were less protective against an intravenous LCMV challenge infection than a comparable number of LCMV-induced memory T cells. LCMV, but not recombinant Listeria-induced memory T cells were able to protect against lethal choriomeningitis by LCMV or a subsequent peripheral infection with recombinant vaccinia virus expressing LCMV-NP. The protective memory after viral and after rLM immunization was paralleled by evidence of LCMV but not rLM antigen persistence on day 15 and 30 after vaccination. These results document a striking difference in protective T cell memory between viral and bacterial vaccines and indicate that rapid T cell-dependent immune protection correlates with antigen persistence.