The human immunodeficiency virus type 1 (HIV-1) is a retrovirus and during infection enters the cell where viral RNA is converted to viral DNA which is subsequently integrated into the host genome. Viral progeny are then secreted from the host plasma membrane by a process of budding. Only two periods in the life cycle of HIV-1, therefore, are amenable for examining the morphological interactions between the virus and its host cell. These are during infection, before the virus loses its structural composition by disassembling to synthesize viral DNA and during viral morphogenesis, as structural components are assembled at the host plasma membrane. Although these time points are critical for the success of HIV-1 they have not been widely studied. To address this, we utilized conventional, immunogold, and high voltage, transmission electron microscopy (TEM) to analyze the structural interactions between HIV-1 and known host cells (T lymphocytes, Jurkat cells) during the time of infection and shedding of virus. Conventional TEM indicated that HIV could enter host cells by several pathways including fusion with the plasma membrane, endocytosis via coated pits and phagocytosis. Specific entry of HIV-1 occurs when gp120, a large glycosylated protein present on the viral envelope, binds to its receptor, CD4, on the surface of host cells (CD4+ T lymphocytes, macrophages, dendritic cells). Immunogold TEM was carried out, therefore, using an antibody directed against gp120 to identify specific uptake of viral particles. Gold-labelled vacuoles were detected in host cells that represented internalized membrane resulting from specific entry of gold-labelled HIV-1 through either fusion with the plasma membrane or receptor mediated endocytosis. High voltage TEM by the use of thick sections, allows more structural information to be examined compared to thin sections and thus provided more morphological details on the attachment of HIV-1 to cells and also detected vesicular sub-structures representing possible transport of macromolecules from the host cell to the budding virion. This study demonstrates that several mechanisms exist for infection of host cells involving both specific (CD4 dependent) and non-specific (CD4 independent via phagocytosis) pathways. These findings indicate that vaccines and/or drugs designed to inhibit specific entry of HIV into host cells by blocking binding of the virus to CD4 may not be effective in combating infection since they would not prevent the non-specific entry of HIV-1 into cells by phagocytosis.