SummaryAimsThe pathology of stroke consists of multiple pro‐death processes, and CD36 has been suggested as a multimodal target to reduce oxidative stress and inflammation in ischemic stroke. Using CD36‐deficient mice and SS‐31, a cell permeable tetrapeptide known to down‐regulate CD36 pathways, the current study investigated whether targeting CD36 is effective in transient and permanent ischemic stroke.MethodsWild‐type or CD36‐deficient mice were subjected to either 30‐min transient or permanent focal ischemic stroke. In parallel, a cohort of mice subjected to either transient or permanent stroke received either vehicle or 5 mg/kg of SS‐31. Monocyte chemoattractant protein‐1 (MCP‐1) and its receptor CCR2, mRNA levels, and infarct volume and percent hemispheric swelling were measured in the postischemic brain.ResultsCD36 deficiency or SS‐31 treatment significantly attenuated MCP‐1 or CCR2 mRNA up‐regulation and injury size in the transient ischemic stroke. However, the approaches failed to show the protective effect in permanent ischemic stroke.ConclusionThe study revealed that targeting CD36 has a beneficial effect on transient but not permanent focal ischemic stroke. The study thus precludes a generalized strategy targeting CD36 in ischemic stroke and suggests careful consideration of types of stroke and associated pathology in developing stroke therapies.