We have investigated the replication of human immunodeficiency virus (HIV) and HIV-induced interferon (IFN) production in human mononuclear phagocytes at 2 different stages of in vitro maturation. Blood monocytes and monocyte-derived macrophages from 6 healthy, HIV-seronegative donors were challenged with HIV1IIIB and HIV2ROD. Freshly separated monocytes produced IFN when inoculated with both HIV types. In these cultures, an inverse correlation was observed between the amount of IFN production and the rate of HIV replication. In contrast to the monocytes, 5-day-old monocyte-derived macrophages did not produce IFN when challenged with HIV, but a significant replication of HIV1IIIB and HIV2ROD was found in all cultures.