Oxidative damage has been reported in Rett syndrome (RTT), a pervasive developmental disorder caused in up to 95% of cases by mutations in the X-linked methyl- CpG binding protein 2 gene. Herein, we have synthesized F2-dihomo-isoprostanes (F2-dihomo-IsoPs), peroxidation products from adrenic acid (22:4 n-6), a known component of myelin, and tested the potential value of F2-dihomo-IsoPs as a novel disease marker and its relationship with clinical presentation and disease progression. F2 - dihomo - IsoPs were determined by gas chromatography/negative-ion chemical ionization tandem mass spectrometry. Newly synthesized F2 - dihomo - IsoP isomers [ent - 7(RS) - F2t - dihomo - IsoP and 17 - F2t - dihomo - IsoP] were used as reference standards. The measured ions were the product ions at m/z 327 derived from the [M-181] precursor ions ( m/z 597) produced from both the derivatized ent - 7(RS) - F2t - dihomo - IsoP and 17 - F2t - dihomo - IsoP. Average plasma F2 - dihomo - IsoP levels in RTT were about one order of magnitude higher than those in healthy controls, being higher in typical RTT as compared with RTT variants, with a remarkable increase of about two orders of magnitude in patients at the earliest stage of the disease followed by a steady decrease during the natural clinical progression. These data indicate for the fi rst time that quantifi cation of F2-dihomo-IsoPs in plasma represents an early marker of the disease and may provide a better understanding of the pathogenic mechanisms behind the neurological regression in patients with RTT