Vitamin E is an essential micronutrient. The primary function of this lipid-soluble antioxidant is to protect membrane phospholipids from oxidation. Whether vitamin E preferentially interacts with polyunsaturated phospholipids to optimize protection of the lipid species most vulnerable to oxidative attack has been an unanswered question for a long time. In this work, we compared the binding of alpha-tocopherol (alpha toc), the form of vitamin E retained by the human body, in bilayers composed of polyunsaturated 1-stearoyl-2-docosahexaenoylphos-phatidylcholine (SDPC, 18:0-22:6PC) and, as a control, monounsaturated 1-stearoyl-2-oleoylphosphatidylcholine (SOPC, 18:0-18:1PC) by umbrella sampling molecular dynamics simulations. From the potential of mean force as a function depth within the bilayer, we find that the binding energy of alpha toc is less in SDPC (Delta G(bind) = 16.7 +/- 0.3 kcal/mol) than that in SOPC (Delta G(bind) = 18.3 +/- 0.4 kcal/mol). The lower value in SDPC is ascribed to the high disorder of polyunsaturated fatty acids that produces a less tightly packed arrangement. Deformation of the bilayer is observed during desorption, indicating that phosphatidylcholine (PC)-PC and alpha toc-PC interactions contribute to the binding energy. Our results do not support the proposal that vitamin E interacts more favorably with polyunsaturated phospholipids.