Hepatic sinusoidal lesions, including peliosis hepatis and sinusoidal dilatation, are frequently observed during human immunodeficiency virus infection. It has been proposed that human immunodeficiency virus itself plays a role in their pathogenesis. To test this hypothesis, we attempted to determine whether liver sinusoidal cells express the CD4 molecule, which behaves as a membrane receptor mediating the binding of human immunodeficiency virus to its target cells. For this purpose, three monoclonal antibodies–OKT4, OKT4a and anti-Leu3a + 3b, binding to different epitopes of the CD4 molecule–were used. All antibodies tested had the same tissue reactivity. On light microscopy, they reacted with most sinusoidal macrophages and in addition gave a continuous labeling of the sinusoidal lining suggestive of endothelial cell reactivity. On ultrastructural examination, the plasma membranes of both sinusoidal macrophages and endothelial cells were labeled. The reactive antigen was characterized by immunoblotting of liver homogenates. A unique band was detected, corresponding to an antigen with an apparent molecular weight of 54,000 Da, comparable to that reported for the CD4 molecule expressed on lymphocytes and monocytes. Therefore combination of structural and immunochemical data makes it possible to assess that both endothelial cells and macrophages of the hepatic sinusoid express the CD4 molecule. Consequently, both cell types constitute putative targets for human immunodeficiency virus and/or human immunodeficiency virus–related lesions. They may be involved in the pathogenesis of liver sinusoidal lesions observed in human immunodeficiency virus infection and may constitute an unsuspected reservoir of the virus. (HEPATOLOGY 1990;12:505–510).