HIV-1 cell-to-cell transmission allows for 2-3 orders of magnitude more efficient viral spread than cell-free dissemination. The high local multiplicity of infection (MOI) observed at cell-cell contact sites may lower the efficacy of antiretroviral therapies (ART). Here we test the efficacy of commonly used antiretroviral inhibitors against cell-to-cell and cell-free HIV-1 transmission. We demonstrate that, while some nucleoside-analog reverse transcriptase inhibitors (NRTI) are less effective against HIV-1 cell-to-cell transmission, most non-nucleoside-analog reverse transcriptase inhibitors (NNRTI), entry inhibitors and protease inhibitors remain highly effective. Moreover, poor NRTIs become highly effective when applied in combinations explaining the effectiveness of ART in clinical settings. Investigating the underlying mechanism, we observe a strict correlation between the ability of individual drugs and combinations of drugs to interfere with HIV-1 cell-to-cell transmission, and their effectiveness against high viral MOIs. Our results suggest that the ability to suppress high viral MOI is a feature of effective ART regimens and this parameter should be considered when designing novel antiviral therapies.