Background: Oxidative stress contributes to Parkinson's disease (PD) etiology. Although previous studies have focused on sources of free radical formation in brain regions affected by PD, less is known regarding changes in lipid composition and the implications for susceptibility to peroxidation. Objective: To assess fatty acid profiles from control and PD tissues that are susceptible to PD pathology but devoid of severe destruction. Methods: We used gas chromatography methods to assess fatty acid profiles from control (n = 10) and PD (n = 9) postmortem tissues. We focused on the anterior cingulate cortex (ACC), a region that accumulates alpha-synuclein, but does not undergo severe destruction, and compared this to the occipital cortex, a region that is pathologically spared. Results: Our data indicate a significant 33% increase in the proportion of polyunsaturated fatty acids (mol%) present in the PD ACC as compared to control ACC. Increases in highly unsaturated 22:5n-6 and 22:6n-3 fatty acids were particularly pronounced (109% and 73%, respectively). Calculation of a peroxidation index (accounting for total fatty acyl double bounds) indicated a 44% increase in susceptibility of the PD ACC to lipid peroxidation compared to control ACC. Such differences were not detected in the occipital cortex from the same donors. Assessment of F2-isprostane levels confirmed that PD tissue lipids were more oxidized than controls. Conclusions: The global composition of fatty acids in the PD ACC is altered in a way that increases susceptibility to peroxidation in a region-specific manner. This has important implications for PD, supporting the oxidative stress hypothesis of PD pathogenesis.