Severe forms of dengue virus disease, known as dengue hemorrhagic fever and dengue shock syndrome, result from an aberrant immune response involving antibody-dependent enhancement of infection, thrombocytopenia, and a loss of vascular integrity, culminating in hemorrhage, shock, and in some cases, death. Several studies have indicated that dengue virus infection results in the induction of apoptosis of certain cells believed to be contributory players in dengue pathogenesis. However, none have specifically examined the role of antibody enhancement in the context of induction of apoptosis. Here, we show that antibody-enhanced dengue virus infection of the FcR-bearing mast cell/basophil KU812 cell line results in a massive induction of apoptosis. Confocal microscopy and flow cytometry indicate two distinct subpopulations consisting of productively infected cells and apoptotic-uninfected bystanders. Apoptosis was found to be caspase-dependent, involving global caspase activation and cleavage of poly-ADP-ribose polymerase and D4-guanosine diphosphate dissociation inhibitor. Additional FcR-bearing cells, including K562, U937, and human mast cell 1 (HMC-1), were analyzed for apoptosis induction following infection. Although all cells displayed high susceptibility to antibody-enhanced dengue virus infection, only cells of a mast cell phenotype (KU812 and HMC-1) were found to undergo apoptosis. Dengue-induced apoptosis of KU812 cells was shown to require antibody-enhanced dengue virus infection by blockade of FcgammaRII. Transfection of KU812 cells with liver/lymph node-specific ICAM-grabbing nonintegrin (SIGN)/dendritic cell-SIGNR was able to overcome the requirement for antibody enhancement with regard to dengue virus infection and apoptosis.