In enzymology, a phospholipid-hydroperoxide glutathione peroxidase (EC 1.11.1.12) is an enzyme that catalyzes the chemical reaction

2 glutathione + a lipid hydroperoxide ${\displaystyle \rightleftharpoons }$ glutathione disulfide + lipid + 2 H₂O

Thus, the two substrates of this enzyme are glutathione and lipid hydroperoxide, whereas its 3 products are glutathione disulfide, lipid, and H₂O.

This enzyme belongs to the family of oxidoreductases, to be specific those acting on a peroxide as acceptor (peroxidases). The systematic name of this enzyme class is glutathione:lipid-hydroperoxide oxidoreductase. Other names in common use include peroxidation-inhibiting protein, PHGPX, peroxidation-inhibiting protein: peroxidase, glutathione, (phospholipid hydroperoxide-reducing), phospholipid hydroperoxide glutathione peroxidase, hydroperoxide glutathione peroxidase, or glutathione peroxidase 4 (GPX4). This enzyme participates in glutathione metabolism.

As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes 2GS3 and 2OBI.