Acute human immunodeficiency virus (HIV) infection is a transient illness that typically presents with mucocutaneous and constitutional symptoms. It is soon followed by seroconversion with the detection of anti-HIV antibodies in the peripheral blood. To better understand the pathogenetic events leading to this clinical picture, we sought to investigate the (immuno)histologic features of the skin rash occurring in an acutely infected person. A skin biopsy of an acutely infected person was investigated histologically and immunohistologically using paraffin-embedded tissue sections. Interface dermatitis with pronounced vacuolization of the basal keratinocytes was a prominent histological finding. The inflammatory infiltrate was composed of CD3+/CD8+ T cells with coexpression of Granzyme B7 and TIA-1, and CD68+ histiocytes/dendritic cells. CD1a+ intraepidermal Langerhans cells (LC) were significantly decreased and individual LC coexpressed HIV-p24 antigens as evidenced in double labeling experiments. HIV-infected LC were demonstrated in close apposition to cytotoxic T cells. This study provides the first definitive evidence for infection of LC at extramucosal sites in this very early stage of disease. Our findings emphasize the critical role of dendritic cells as a virus reservoir and the skin as a major site of HIV replication during the course of the disease.