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In Transmissible Spongiform Encephalopathies (TSEs), the localization of the prion protein in the neuronal membrane lipid rafts (LR) seems to play a role in sustaining the protein misfolding. Changes in membrane properties, due to altered lipid composition, affect their organization and interaction between lipids and protein therein, and consequently also membrane resident protein functionality; dietary polyunsaturated fatty acids (PUFAs), gangliosides and cholesterol seem to influence these processes. Aims In this work, the influence of administration of different feed, able to change the composition of lipid membrane, on the clinical progression of prion disease was studied. Main methods The activity of three diets (hyperlipidic with 6% fats; hypolipidic with 0.1% fats; and purified with 4% fats) was tested in CD1 mouse model experimentally infected with RML scrapie strain. Presence and distribution of typical central nervous system (CNS) lesions and deposits of PrPsc were evaluated by histopathological analysis and immunohistochemistry. Analysis of lipids was performed in homogenate and insoluble brain fraction of the neuronal membrane rich in LR. Key findings Results show that a diet with a different lipid level has not a significant role in the development of the scrapie disease. All infected mice fed with different diets died in the same time span. Histology, immunohistochemistry, and neuropathological analyses of the infected brains did not show significant differences between animals subjected to different diets. Significance Independently of the diet, the infection induced a significant modification of the lipid composition in homogenates, and a less noticeable one in insoluble brain fraction.