IRF4 is a transcription factor from the IRF factor family that plays pivotal roles in the differentiation and function of T and B lymphocytes. Although IRF4 is also expressed in dendritic cells (DCs) and macrophages, its roles in these cells in vivo are not clearly understood. In this study, conditional knockout mice that lack IRF4 in DCs or macrophages were generated and infected with Leishmania major. Mice lacking DC expression of IRF4 showed reduced footpad swelling compared with C57BL/6 mice, whereas those lacking IRF4 in macrophages did not. Mice with IRF4-deficient DCs also showed reduced parasite burden, and their CD4(+) T cells produced higher levels of IFN-γ in response to L. major Ag. In the draining lymph nodes, the proportion of activated CD4(+) T cells in these mice was similar to that in the control, but the proportion of IFN-γ-producing cells was increased, suggesting a Th1 bias in the immune response. Moreover, the numbers of migrating Langerhans cells and other migratory DCs in the draining lymph nodes were reduced both before and postinfection in mice with IRF4 defects in DCs, but higher levels of IL-12 were observed in IRF4-deficient DCs. These results imply that IRF4 expression in DCs inhibits their ability to produce IL-12 while promoting their migratory behavior, thus regulating CD4(+) T cell responses against local infection with L. major.