Introduction: Neuroimaging studies demonstrate that not only the lesions of malformations of cortical development (MCD) but also the normal-appearing parenchyma (NAP) present metabolic impairments, as revealed with H-1-MRS. We have previously detected biochemical disturbances in MCD lesions with phosphorus-31 magnetic resonance spectroscopy (P-31-MRS). Our hypothesis is that pH abnormalities extend beyond the visible lesions. Methods: Three-dimensional P-31-MRS at 3.0 T was performed in 37 patients with epilepsy and MCD, and in 31 matched-control subjects. The patients were assigned into three main MCD subgroups: cortical dysplasia (n = 10); heterotopia (n = 14); schizencephaly/polymicrogyria (n = 13). Voxels (12.5 cm(3)) were selected in five homologous regions containing NAP: right putamen; left putamen; frontoparietal parasagittal cortex; right centrum semiovale; and left centrum semiovale. Robust methods of quantification were applied, and the intracellular pH was calculated with the chemical shifts of inorganic phosphate (Pi) relative to phosphocreatine (PCr). Results: In comparison to controls and considering a Bonferroni adjusted p-value