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Background and Purpose: HDAC9 polymorphisms rs2107595 and rs11984041 are associated with large vessel atherosclerotic stroke. HDAC9 regulates gene expression and is expressed in circulating leukocytes involved in atherosclerosis. In this study, we sought to determine whether HDAC9 single nucleotide polymorphisms (SNPs) rs2107595 or rs11984041 influence gene expression in blood of patients with large vessel atherosclerotic stroke (LVAS).Methods: In 155 patients (43 LVAS and 112 vascular risk factor control) HDAC9 was genotyped for SNPs rs2107595 and rs11984041. RNA was isolated from whole blood and gene expression differences between HDAC9 risk allele positive and risk allele negative LVAS and control patients identified using human transcriptome microarrays. Pathway analysis was performed to identify canonical pathways and molecular functions associated with HDAC9 SNPs in LVAS.Results: In rs2107595 risk allele positive LVAS patients there were 155 genes differentially expressed compared to SNP negative patients (fold change > |1.2|, p<0.05). Over represented pathways corresponded to IL6 signaling, cholesterol efflux and platelet aggregation. In rs11984041 risk allele positive LVAS patients there were 419 genes differentially expressed genes compared to risk allele negative patients (fold change > |1.2|, p<0.05). Over represented pathways included NF-?B signaling, T cell response and macrophage activation.Conclusions: Polymorphisms in HDAC9 are associated with differences in gene expression in blood cells of patients with LVAS. The risk alleles in HDAC9 may contribute to functional differences in peripheral immune cells involved in stroke related atherosclerosis, plaque stability, and inflammation.