Hypersensitivity to mosquito bites (HMB) is characterized by intense local skin reactions and systemic symptoms, such as high fever, lymphadenopathy and hepatosplenomegaly. Half of the patients reported died of hemophagocytic syndrome or lymphocyte proliferative disorders. Clinical and laboratory studies have revealed that HMB occurs in association with natural killer (NK) cell lymphocytosis related to chronic Epstein-Barr virus (EBV) infection. Recent studies have clarified the unique pathogenic mechanism of this mysterious disease, and demonstrated the close relationship between HMB and EBV-carrying NK cell lymphocytosis; i.e., CD4(+) T cells from the patients markedly responded to mosquito salivary gland extracts, and the CD4(+) T cells stimulated by mosquito bites may play a key role in the development of HMB and NK cell oncogenesis via the induction of EBV reactivation and EBV-oncogene expression, respectively.