Reactive lipid hydroperoxides formed by lipoxygenases and cyclooxygenases can contribute to disease through cellular oxidative damage. Several selenoproteins have lipid hydroperoxidase activity, including glutathione peroxidase 4, thioredoxin reductase, and selenoprotein P (SelP). SelP is an extracellular glycoprotein that functions both in selenium distribution and has an antioxidant activity. The major objective of this study was to determine if an SelP, at physiological concentrations and in selenium replete media, possessed hydroperoxidase activity directed at lipid hydroperoxides generated from the metabolism of arachidonic acid by 15-lipoxygenase-1 (15-LOX-1). An SelP displayed in vitro lipid hydroperoxidase activity of 15-hydroperoxyeicosatetraenoic acid (15-HpETE), attenuated 15-HpETE oxidation in cellular assays, and in transcellular assay when 15-LOX-1 is metabolically active. These results suggest that an SelP can function as an antioxidant enzyme against reactive lipid intermediates formed during inflammation, but an SelP has modest activity. Nevertheless, this effect may help protect cells against the oxidative damage induced by these lipid metabolites.