FTY720 inhibits lymphocyte emigration from lymphoid organs to peripheral blood by binding one of the sphingosine-1-phosphate (S1P) receptors, S1P(1). We investigated the effects of FTY720 in relation to murine contact hypersensitivity (CHS). CHS was impaired by FTY720 when administered during the sensitization but not the elicitation phase. Consistently, adoptive transfer of immunized lymph node cells from mice treated with FTY720 during the sensitization phase was virtually incapable of inducing CHS response in recipients. FTY720 decreased the number of blood CD44(-) -naive T cells markedly and that of CD44(+) memory T cells modestly. Among memory T cells, the CD62L(-) effector memory subset was more resistant to FTY720 than the CD62L(+) central memory subset. Accordingly, the level of S1P chemotactic response was high in naive T cells, marginal in effector memory T cells, and very low in central memory T cells. Consistently, the S1P(1) mRNA expression level was much lower in memory T cells than in naive T cells. These findings demonstrate that S1P-S1P(1) signaling is essential for recirculation of naive T cells. FTY720 seems to decrease the incidence of interactions between antigen-loaded dendritic cells and circulating naive T-cell clones in the lymph nodes, thereby depressing the sensitization of naive T cells in CHS.