Children who experience secondary dengue virus (DV) infections are at increased risk for dengue hemorrhagic fever. To study the effect of preexisting T cell responses to DV on the severity of secondary virus infection, peripheral blood mononuclear cells (PBMC) from 10 subsequently hospitalized and 12 nonhospitalized Thai schoolchildren were stimulated with inactivated dengue antigens, and proliferation of interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha responses of the preinfection PBMC were measured. Proliferation responses were observed in 11 subjects, and IFN-gamma responses were seen in 12 subjects, 6 of whom showed broad serotype cross-reactive IFN-gamma responses. TNF-alpha responses were detected exclusively in 4 hospitalized subjects. Four PBMC samples that showed neither proliferation nor cytokine responses to any dengue antigen were from nonhospitalized subjects. This study, thought to be the first to investigate T cell responses to DV in preinfection PBMC, suggests that the pattern of preexisting T cell responses influences the risk for severe disease.