AbstractObjective:Hyperlipidemia exacerbates ischemic stroke outcome and increases CD36 expression in the postischemic brain as well as in peripheral monocytes/macrophages. By exchanging bone marrow‐derived cells between CD36‐expressing and CD36‐deficient mice, this study investigates the contribution of peripheral CD36 in comparison with that of brain CD36 to stroke pathology in hyperlipidemia.Methods:Following bone marrow transplantation, mice were fed a high‐fat diet for 11 weeks and then subjected to ischemic stroke. Stroke outcome, expression of brain CD36, monocyte chemoattractant protein‐1 (MCP‐1), CCR2, and plasma MCP‐1 levels were determined at 3 days postischemia. CD36 and CCR2 expression were also determined in splenocytes incubated with serum obtained from CD36‐expressing or CD36‐deficient mice.Results:Infiltrating immune cells from the periphery are the major source of CD36 in the postischemic brain and contribute to stroke‐induced brain injury. This CD36 effect was dependent on the modulation of MCP‐1 and CCR2 expression in peripheral immune cells as well as CD36‐expressing cells in the host brain.Interpretation:This study demonstrates that CD36 expressed in the periphery and brain synergize in ischemic brain injury through regulation of the MCP‐1/CCR2 chemokine axis in hyperlipidemic conditions. ANN NEUROL 2012;71:753–764