Update information. Hyperlipidemia is a chronic disease characterized by elevated blood cholesterol and triglyceride and there have been accumulated evidence that the disease might affect brain functions. Here we report on a proteomic analysis of the brain proteins in hyperlipidemic mice. Hyperlipidemia was successfully induced in mice by 20 weeks of a high-fat diet (HFD) feeding. Control group (normal diet) and HFD with simvastatin treatment (SIM) group were established accordingly. The proteins were extracted from the two hemispheres of the animal cerebrums of the three groups (3 mice per group) and subjected to shotgun analysis using nano-LC-MS/MS. A total of 4422 proteins were identified and quantified in at least half of the samples, among which 324 proteins showed significant difference (fold change >1.5 or <0.67, p <0.05) in at least one of the four types of comparisons (left cerebrums of model versus control, right cerebrums of model versus control, left cerebrums of SIM versus model, right cerebrums of SIM versus model). Bioinformatic analysis revealed a major part of the dys-regulated proteins were involved in lipid-related processes such as lipid clearance and biosynthesis, and nerve-related events such as neuroinflammation, brain development, learning and memory. It is interesting that some of the proteins with functions in learning and memory were more susceptible to hyperlipidemia in the right cerebrum hemisphere than in the left. We expect this work would provide useful information to improve the understanding of the effect and mechanism of hyperlipidemia on brain protein composition and functions.