Memory T cells can be divided into central-memory (T(CM)) and effector-memory (T(EM)) cells, which differ in their functional properties. Although both subpopulations can persist long term, it is not known whether they are maintained by similar mechanisms. We used in vivo labeling with deuterated glucose to measure the turnover of CD4(+) T cells in healthy humans. The CD45R0(+)CCR7(-) T(EM) subpopulation was shown to have a rapid proliferation rate of 4.7% per day compared with 1.5% per day for CD45R0(+)CCR7(+) T(CM) cells; these values are equivalent to average intermitotic (doubling) times of 15 and 48 d, respectively. In contrast, the CD45RA(+)CCR7(+) naive CD4(+) T cell population was found to be much longer lived, being labeled at a rate of only 0.2% per day (corresponding to an intermitotic time of approximately 1 yr). These data indicate that human CD4(+) T(EM) cells constitute a short-lived cell population that requires continuous replenishment in vivo.