A comparative study has been carried out on the general reactivity of lipid hydroperoxides in liposomes, biological membranes and lipoproteins with two Se-dependent peroxidases: Glutathione Peroxidase (GPX) and Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPX). While PHGPX reduces all hydroperoxides derived from phospholipids, cholesterol and cholesterol esters, GPX reduces only fatty acid hydroperoxides released after treatment of phospholipid hydroperoxides with phospholipase A2. These findings highlight the role of PHGPX in protecting biomembranes from peroxidative damage and add new insight into how cholesterol hydroperoxides are detossified in cells.