CD1d is an MHC class I-like surface molecule that presents endogenous glycoplipid antigens. The effect of HIV infection on CD1d surface expression has not yet been reported. FACS analysis revealed significantly lower levels of CD1d on CD14(+) monocytes from HIV-infected subjects compared to HIV-infected subjects on HAART and healthy controls. CD1d expression correlated inversely with viral load in infected individuals. CD1d surface expression on human cell lines was downregulated after infection with M-tropic HIV, T-tropic HIV, or after exposure to HIV gp120 in vitro. These data suggest that CD1d-mediated responses are altered during HIV infection and may thus contribute to the global immunodeficiency seen in these patients.