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BACKGROUND AND PURPOSE Despite its contradictory clinical performance, Veklury® (remdesivir) has a pivotal role in COVID-19 therapy. Possible contributions of the vehicle sulfobutylether-β-cyclodextrin (SBECD) to Veklury® effects are neglected and the powder and solution formulations of Veklury® are treated equivalently despite their different vehicle content. Our objective was to study Veklury® effects on initial membrane-coupled events of SARS-CoV-2 infection and highlight the cholesterol depletion-mediated active role of SBECD. EXPERIMENTAL APPROACH Using time-correlated flow cytometry and quantitative 3-dimensional confocal microscopy we studied early molecular events of SARS-CoV-2-host cell membrane interactions. KEY RESULTS Veklury® and different cholesterol-depleting cyclodextrins (CDs) reduced binding of the spike receptor binding domain (RBD) to ACE2 and spike trimer internalization for Wuhan-Hu-1, Delta and Omicron variants. Correlations of these effects with cholesterol-dependent changes in membrane structure and decreased, lipid raft-dependent ACE2-TMPRSS2 interaction establish that SBECD is not simply a vehicle, but also an effector in Veklury® due to its cholesterol-depleting potential. Veklury® solution inhibited RBD binding more efficiently due to its two-times higher SBECD content. The CD-induced inhibitory effects were more prominent at lower RBD concentrations and in cells with lower endogenous ACE2 expression suggesting that the supportive CD actions can be even more pronounced during in vivo infection when viral load and ACE expression are typically low. CONCLUSION AND IMPLICATIONS Our findings call for the differentiation of Veklury® formulations in meta-analyses of clinical trials, potentially revealing neglected benefits of the solution formulation, and also raise the possibility of adjuvant CD therapy, even at higher doses, in COVID-19.