Dengue type 2 virus replication was detected in the U-937 human monocyte cell line when the virus inoculum and the culture medium contained flavivirus antibodies diluted beyond their neutralizing titers. This was in marked contrast to yellow fever virus, which replicated very well in the absence of antibodies; however, 10-fold-higher yields of yellow fever virus could be obtained in the presence of flavivirus antibodies. These infection-enhancing antibodies were obtained from either a dengue type 2 human antiserum or reference hyperimmune obtained from either a dengue type 2 human antiserum or reference hyperimmune mouse ascitic fluid. The infection enhancement phenomenon, previously shown to be due to infection of Fc receptor-bearing cells with virus-antibody complexes, was completely blocked by preincubation of the cells with aggregated gamma globulin. The blocking results suggested an Fc receptor-mediated infection of the U-937 cells as well. A panel of monoclonal antibodies, previously characterized as either virus type specific or flavivirus cross-reactive and with mouse immunoglobulin subclasses G1 and G2a in both categories, were tested for their infection enhancement characteristics. A type-specific neutralizing monoclonal antibody preparation that was diluted beyond its neutralization titer did not cause infection enhancement, nor did low-level neutralizing monoclonal antibodies that were dengue serotype specific by the hemagglutination inhibition test. Only flavivirus cross-reactive monoclonal antibodies caused infection enhancement, irrespective of whether the immunoglobulins were G1 or G2a. These cross-reactive flavivirus determinants may reside at the tips of the glycoprotein projections on the virus particles, enabling the Fc ends of the cross-reactive antibodies attached to these determinants to interact with Fc receptors on susceptible cells.