The implication of lipid peroxidation in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) derive from high abundance of peroxidation- prone polyunsaturated fatty acids in central nervous system and its relatively low antioxidant content. In the present work, we evaluated the effect of dietary changes aimed to modify fatty acid tissular composition in survival, disease onset, protein, and DNA oxidative modifications in the hSODG93A transgenic mice, a model of this motor neuron disease. Both survival and clinical evolution is dependent on dietary fatty acid unsaturation and gender, with high unsaturated diet, leading to loss of the diseasesparing effect of feminine gender. This was associated with significant increases in protein carbonyl and glycoxidative modifications as well as non-nuclear 8-oxo-dG, a marker of mitochondrial DNA oxidation. Comparison of these data with cH2AX immunostaining, a marker of DNA damage response, suggests that the highly unsaturated diet-blunted mitochondrial–nuclear free radical dependent crosstalk, since increased 8-oxo-dG was not correlated with increased DNA damage response. Paradoxically, the highly unsaturated diet led to lower peroxidizability but higher antiinflammatory indexes. To sum up, our results demonstrate that high polyunsaturated fatty acid content in diets may accelerate the disease in this model. Further, these results reinforce the need for adequately defining gender as a relevant factor in ALS models, as well as to use structurally characterized markers for oxidative damage assessment in neurodegeneration. ; Supported by the Spanish Ministry of Science and Innovation [CENIT Program, BFU2009-11879/BFI and AGL2006- 1243] the Autonomous Goverment of Catalunya [2009SGR-735] and the Spanish Ministry of Health [FIS 08-1843, 11-01532 to M.P-O and FIS13-00584 to RP]. Supported also by the COST B-35 Action and the Fundació Miquel Valls. D.C. is a predoctoral fellow from Spanish Ministry of Health [FI08-00707]. O.R-N. and R. C. received a predoctoral fellowship from Autonomous Government of Catalonia.