Glomerular visceral epithelial cells (podocytes) play a critical role in the maintenance of glomerular permselectivity. Podocyte injury, manifesting as proteinuria, is the cause of many glomerular diseases. We reported previously that calcium-independent phospholipase A(2) (iPLA(2)) is cytoprotective against complement-mediated glomerular epithelial cell injury. Studies in iPLA(2) KO mice have demonstrated an important role for iPLA(2) in mitochondrial lipid turnover, membrane structure, and metabolism. The aim of the present study was to employ iPLA(2) KO mice to better understand the role of iPLA(2) in normal glomerular and podocyte function as well as in glomerular injury. We show that deletion of iPLA(2) did not cause detectable albuminuria; however, it resulted in mitochondrial structural abnormalities and enhanced autophagy in podocytes as well as loss of podocytes in aging KO mice. Moreover, after induction of anti-glomerular basement membrane nephritis in young mice, iPLA(2) KO mice exhibited significantly increased levels of albuminuria, podocyte injury, and loss of podocytes compared with wild type. Thus, iPLA(2) has a protective functional role in the normal glomerulus and in glomerulonephritis. Understanding the role of iPLA(2) in glomerular pathophysiology provides opportunities for the development of novel therapeutic approaches to glomerular injury and proteinuria.