Plasma lipid levels have been known to be risk factors for atherosclerosis for decades, and in recent years it has become accepted that inflammation is a crucial event in the pathogenesis of atherosclerosis. In this study, we investigated the relationship between plasma lipids and leukocytes by profiling and analyzing leukocyte gene expression in response to plasma lipid levels. We discovered several interesting patterns of leukocyte gene expression: (1) the expression of a number of immune response- and inflammation-related genes are correlated with plasma lipid levels; (2) genes involved in lipid metabolism and in the electron transport chain were positively correlated with triglycerides and low-density lipoprotein cholesterol (LDL) levels, and negatively correlated with high-density lipoprotein cholesterol (HDL) levels; (3) genes involved in platelet activation were negatively correlated with HDL levels; (4) transcription factors regulating lipogenesis-related genes were correlated with plasma lipid levels; (5) a number of genes correlated with plasma lipid levels were found to be located in the regions of known quantitative trait loci (QTLs) associated with hyperlipemia. Our findings suggest that leukocytes respond to changing plasma lipid levels by regulating a network of genes, including genes involved in immune response, and lipid and fatty acid metabolism.