Under conditions of oxidative stress, cholesterol aggregates into discrete membrane bilayer domains that precipitate the formation of extracellular crystals, a hallmark feature of the advanced atheroma in cardiovascular disease. Molecular intervention using membrane-directed antioxidants, such as polyphenolic esters, alkylated to increase their lipophilicity and bioavailability, may reduce cholesterol domain formation and associated pathology. In this study, we tested the effects of rosmarinic acid (R0) and rosmarinic esters, with alkyl chain lengths ranging from 4 to 16 carbons (R4-R16), on membrane lipid oxidation and cholesterol domain formation. Model membranes were prepared as binary mixtures of dilinoleoylphosphatidylcholine and cholesterol (at a cholesterol-to-phospholipid mole ratio of 0.6:1), in the absence or presence of each of the various rosmarinic compounds, and exposed to oxidative conditions for up to 72 hr. Changes in lipid hydroperoxide (LOOH) and cholesterol domain formation were measured using iodometric and small angle x-ray diffraction approaches, respectively. Rosmarinic acid and the various esters were observed to have differential effects on LOOH formation based on alkyl chain length. R8 had the greatest antioxidant effect, reducing LOOH levels by 60 ± 18% as compared to vehicle. R8 also inhibited cholesterol domain formation. By contrast, R0 and R16 failed to inhibit LOOH formation (6 ± 19% reduction, 5 ± 13% increase compared to vehicle, respectively), resulting in cholesterol domain formation. These data indicate that the membrane antioxidant potential of rosmarinic acid esters is dependent, in a nonlinear manner, on alkyl chain length. The mechanism for this effect is attributed to the influence of alkyl chain length on the optimal depth of the polyphenols into the lipid bilayer. These findings provide insight into novel atheroprotective benefits of polyphenol esters that are dependent on their membrane location.