CD14(+)CD16(+) monocytes are an important cellular target for HIV-1 entry and expand in the peripheral blood of HIV-infected individuals. Because CD14(+)CD16(+) monocytes are a heterogeneous population and consist of CD14(high)CD16(+) and CD14(low)CD16(+) subsets, we evaluated the effects of HIV infection on distinct subsets of CD16(+) monocytes.Untreated HIV-infected patients were recruited to investigate the relationship between the proportions of monocyte subsets with plasma viral loads and CD4(+) T-cell counts. Patients receiving highly active antiretroviral therapy (HAART) were followed up in a cross-sectional and a longitudinal study.Compared with CD14(low)CD16(+), CD14(high)CD16(+) monocytes showed higher levels of CD64 and HLA-DR antigens, which imply that these 2 distinct subsets have different immunoregulatory phenotypes. In HAART-naive patients, elevated proportions of CD14(high)CD16(+) monocytes were correlated with increased viral loads and decreased CD4(+) T-cell counts, whereas CD14(low)CD16(+) monocytes did not show such correlation with disease progression. Of importance, HAART recovered the proportion of CD14(high)CD16(+) monocytes, whereas CD14(low)CD16(+) monocytes did not decrease during 1 year of antiviral therapy.Taken together, our observations elucidate distinct immune responses of monocyte subsets during HIV infection and antiviral therapy and provide new insight into the roles of innate immunity in HIV-related pathogenesis.