Human monocytes appear to be very important in the pathogenesis of dengue infection. They are thought to be the most active sites of virus replication during dengue infection. We have analysed interferon (IFN) production by dengue virus from peripheral blood mononuclear cells (PBMC). IFN activity was first detected at 12 h after infection of monocytes and reached a maximum level by 48 h. Non-adherent PBMC depleted of monocytes did not produce detectable levels of IFN, and did not contain dengue antigen-positive cells after exposure to dengue virus. The IFN produced was characterized as IFN-alpha by neutralization tests using specific antisera to HuIFN-alpha, HuIFN-beta and HuIFN-gamma, and by radioimmunoassay. The culture fluids of dengue virus-infected monocytes, which contained IFN-alpha, were able to inhibit infection of human monocytes by dengue virus. These results suggest that IFN-alpha produced by dengue virus-infected monocytes may play an important role in controlling primary dengue virus infection.