CCR7(+ )central memory (T(CM)) CD4(+) T cells play a central role in long-term immunological memory. Recent reports indicate that a proportion of CD4(+) T(CM) is able to produce effector cytokines. The phenotype and the role of this subset remain unknown. We characterized cytokine-producing human CD4(+) T(CM) specific for cleared protein and persistent viral Ag. Our results demonstrate that the type of Ag stimulation is a major determinant of CD4(+) T(CM) differentiation. CMV-specific T(CM) were significantly more differentiated than protein Ag-specific T(CM) and included higher proportions of IFN-gamma-producing cells. The expression of killer cell lectin-like receptor G1 (KLRG1) by protein Ag- and CMV-specific T(CM) was associated with increased production of effector cytokines. KLRG1(+) T(CM) expressed high levels of CD127, suggesting that they can survive long term under the influence of IL-7. The induction of KLRG1(+) T(CM) may therefore represent an important target of vaccination against pathogens controlled by cellular immune responses.