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2 Adhesion molecules are known to play major roles in the initiation and stabilization of cell-to-cell contacts during the immunological response. HIV-1 exploits those interactions to facilitate infection and propagation processes. The primary objective of the present study was to investigate the ability of antagonists specific for the lymphocyte function-associated antigen-1 (LFA-1) to diminish HIV-1 infection and transmission. We demonstrate here that LFA-1 antagonists can significantly reduce HIV-1 replication in primary human cells and virus propagation by affecting cell-to-cell interactions. Moreover, inhibition of LFA-1-mediated adhesion events also potentiates the antiviral efficacy of the peptide fusion inhibitor T-20. Altogether our data suggest that LFA-1 antagonists represent promising antiviral agents. Anti-adhesion therapy could be considered as a complementary strategy targeting cellular functions essential for HIV-1 spreading and against which the combined therapy currently used displays a limited efficacy.