Persistent high fever is one of the most typical clinical symptoms in dengue virus (DV)–infected patients. However, the source of endogenous pyrogen (eg, IL-1β) and the signaling cascade leading to the activation of inflammasome and caspase-1, which are essential for IL-1β and IL-18 secretion, during dengue infection have not been elucidated yet. Macrophages can be polarized into distinct phenotypes under the influence of GM-CSF or M-CSF, denoted as GM-Mφ and M-Mφ, respectively. We found that DV induced high levels of IL-1β and IL-18 from GM-Mφ (inflammatory macrophage) and caused cell death (pyroptosis), whereas M-Mφ (resting macrophage) did not produce IL-1β and IL-18 on DV infection even with lipopolysaccharide priming. This observation demonstrates the distinct responses of GM-Mφ and M-Mφ to DV infection. Moreover, up-regulation of pro-IL-1β, pro-IL-18, and NLRP3 associated with caspase-1 activation was observed in DV-infected GM-Mφ, whereas blockade of CLEC5A/MDL-1, a C-type lectin critical for dengue hemorrhagic fever and Japanese encephalitis virus infection, inhibits NLRP3 inflammasome activation and pyrotopsis in GM-Mφ. Thus, DV can activate NLRP3 inflammasome via CLEC5A, and GM-Mφ plays a more important role than M-Mφ in the pathogenesis of DV infection.