Intestinal and hepatic lipid metabolism plays an essential role in regulating plasma lipid levels. These lipids are mobilized on apolipoprotein B (apoB)-containing lipoproteins and their plasma homeostasis is maintained by balancing production and catabolism. Microsomal triglyceride transfer protein (MTP) which is expressed mainly in the intestine and liver plays an essential role in regulating the assembly and secretion of apoB-lipoproteins. Any imbalance in the production or clearance of lipoproteins leads to hyperlipidemia which is a major risk factor for atherosclerosis, obesity, diabetes, and metabolic syndrome. Here, we identify a new role of inositol-requiring transmembrane kinase/endoribonuclease 1\alpha (IRE1\alpha) in the regulation of plasma lipids. We generated intestine specific IRE1\alpha knockout mice to study whether intestinal IRE1\alpha regulates plasma lipids by modulating intestinal lipid absorption. Intestine specific deletion of Ire1a gene in mice fed chow diet, significantly reduced plasma cholesterol and triglycerides by 29% and 43% in Ire1a{}^{\mathrm{-}\mathit{}\mathrm{/}\mathrm{-}} mice (P 0.01 & P 0.001, respectively). These changes were not associated with any alteration of MTP activity nor its mRNA expression. On the other hand, Western diet increased plasma triglyceride by 37% (P 0.01) without affecting total plasma cholesterol in Ire1a{}^{\mathrm{-}\mathit{}\mathrm{/}\mathrm{-}} mice. Interestingly, this effect was associated with a significant increase in the intestinal MTP activity and its mRNA expression (25%, P 0.01 and 70%, P 0.05, respectively). Collectively, our findings reveal key role of intestinal IRE1\alpha in the regulation of plasma lipids that may provide a therapeutic target for disorders of lipid metabolism.