Interleukin (IL)-18 generates T helper 1-type immunity and inhibits human immunodeficiency virus type 1 (HIV-1) in primary cells in vitro. Because IL-18 may participate in HIV-1 containment, whole-blood IL-18 levels were measured in 20 healthy control subjects and longitudinally in 28 subjects with early HIV-1 infection. Compared with those in control subjects, IL-18 levels were higher during early HIV-1 infection, and IL-18 levels predicted reduced CXCR4 HIV-1 coreceptor expression and diminished interferon (IFN)- gamma levels. By contrast, a direct association between IL-18 and IFN- gamma levels was observed in blood stimulated with lipopolysaccharide. During early HIV-1 infection, IL-18 may regulate HIV-1 coreceptor expression and have antiretroviral activity.