Ca²⁺-independent phospholipase A₂ (GVIA iPLA₂) has gained increasing interest recently as it has been recognized as a participant in biological processes underlying diabetes development and autoimmune-based neurological disorders. The development of potent GVIA iPLA₂ inhibitors is of great importance because only a few have been reported so far. We present a novel class of GVIA iPLA₂ inhibitors based on the β-lactone ring. This functionality in combination with a four-carbon chain carrying a phenyl group at position-3 and a linear propyl group at position-4 of the lactone ring confers excellent potency. trans-3-(4-Phenylbutyl)-4-propyloxetan-2-one (GK563) was identified as being the most potent GVIA iPLA₂ inhibitor ever reported ( X_I(50) 0.0000021, IC₅₀ 1 nM) and also one that is 22 000 times more active against GVIA iPLA₂ than GIVA cPLA₂. It was found to reduce β-cell apoptosis induced by proinflammatory cytokines, raising the possibility that it can be beneficial in countering autoimmune diseases, such as type 1 diabetes.