The four serotypes of dengue virus (a mosquito-borne flavivirus) cause an acute febrile illness (dengue fever) or a more prolonged illness with plasma leakage resulting in hypovolemia (dengue hemorrhagic fever). Hemorrhage may accompany either. Epidemiologic data suggest a role for dengue antibodies in pathogenesis. Computer analysis revealed a 20-residue region of similarity in amino acid sequence between the dengue type 4 envelope glycoprotein (E) and a family of clotting factors, including plasminogen, the prime mediator of fibrinolysis. By use of synthetic peptides in ELISA, E antibodies that potentially bind plasminogen were detected in 75% of 40 Thai patients acutely infected with dengue virus type 1, 2, 3, or 4. Plasminogen cross-reactivity of dengue antibodies was shown to be specific for the related sites in E and plasminogen. The dengue E sequence with similarity to plasminogen is largely conserved within the currently known flavivirus E sequences. However, 15 Thai patients hospitalized for illness caused by Japanese encephalitis virus (a flavivirus not associated with hemorrhage) did not develop plasminogen-cross-reactive antibodies, and this finding correlated with failure of Japanese encephalitis virus antibodies to bind to the plasminogen-cross-reactive site in E.