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Cell-based therapies have the potential to transform the treatment of many diseases. One of the key challenges relating to cell therapies is to modify the cell surface with molecules to modulate cell functions such as targeting, adhesion, migration, and cell–cell interactions, or to deliver drug cargos. Noncovalent insertion of lipid-based amphiphilic molecules on the cell surface is a rapid and nontoxic approach for modifying cells with a variety of bioactive molecules without affecting the cellular functions and viability. A wide variety of lipid amphiphiles, including proteins/peptides, carbohydrates, oligonucleotides, drugs, and synthetic polymers have been designed to spontaneously anchor on the plasma membranes. These molecules typically contain a functional component, a spacer, and a long chain diacyl lipid. Though these molecular constructs appeared to be stably tethered on cell surfaces both in vitro and in vivo under static situations, their stability under mechanical stress (e.g., in the blood flow) remains unclear. Using diacyl lipid-polyethylene glycol (lipo-PEG) conjugates as model amphiphiles, here we report the effect of molecular structures on the amphiphile stability on cell surface under mechanical stress. We analyzed the retention kinetics of lipo-PEGs on erythrocytes in vitro and in vivo and found that under mechanical stress, both the molecular structures of lipid and the PEG spacer have a profound effect on the membrane retention of membrane-anchored amphiphiles. Our findings highlight the importance of molecular design on the dynamic stability of membrane-anchored amphiphiles.