Abstract: Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis, and they may also play an important role in the generation of intracellular free radicals. The group IV cytosolic form of phospholipase A2 (cPLA2) is regulated by changes in intracellular calcium concentration, and the enzyme preferentially acts to release arachidonic acid esterified at the sn‐2 position of phospholipids. We examined the susceptibility of mice carrying a targeted mutation of the cPLA2 gene to 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced neurotoxicity. Mutant mice have no functional cPLA2 activity. Mice that were homozygous for the mutation (cPLA2−/−) were significantly resistant to MPTP‐induced dopamine depletion as compared with littermate control (cPLA2+/+) and heterozygous mice (cPLA2+/−). These findings provide evidence that cPLA2 plays a role in MPTP neurotoxicity and suggest that cPLA2 may play a role in the development of Parkinson's disease in humans.