In the present study, we demonstrated that expression of the LFA-1 molecule is necessary for cell fusion and syncytia formation in human immunodeficiency virus (HIV)-infected CD4+ T lymphocytes. In contrast, the lack of expression of LFA-1 does not influence significantly cell-to-cell transmission of HIV. In fact, LFA-1- T lymphocytes obtained from a leukocyte adhesion deficiency patient were unable to fuse and form syncytia when infected with HIV-1 or HIV-2, despite the fact that efficiency of HIV infection (i.e., virus entry, HIV spreading, and levels of virus replication) was comparable with that observed in LFA-1+ T lymphocytes. In addition, we provide evidence that LFA-1 by mediating cell fusion contributes to the depletion of HIV-infected CD4+ T lymphocytes in vitro.