Delayed-type hypersensitivity (DTH) to dengue virus type 4 in mice is described. The DTH reaction (measured by footpad swelling) was maximal at 24 hr after challenge and was enhanced significantly when mice were pretreated with cyclophosphamide. The response was maximal six days after infection with an immunizing dose of approximately 10(7.3) 50% lethal doses per mouse. Histologic examination of the test footpad showed a predominantly mononuclear cell infiltrate at 24 hr after challenge. fibrin deposition was also noted. DTH reactivity was transferable to normal mice by injection of immune spleen cells but not of immune serum. The DTH reaction was apparently specific for dengue virus type 4 because significantly lower responses were detected when dengue virus types 1-3 and Japanese encephalitis virus were used as challenge antigens in mice infected with dengue virus type 4. The probable importance and significance of these findings in relation to the host immune response and the pathogenesis of dengue virus infection are discussed.