Rationale: Intestinal alkaline phosphatase (IAP) is secreted by enterocytes and is present on the apical surface. It not only detoxifies bacterial endotoxin lipopolysaccharide (LPS) in the gut lumen and limits intestinal inflammation but also restricts translocation of LPS into systemic circulation. Diet-induced intestinal barrier dysfunction and subsequent development of metabolic endotoxemia seen in diabetes and heart disease is associated with reduced IAP levels. To examine the direct effects of increased IAP expression on barrier function and development of metabolic diseases, we developed intestine-specific IAP transgenic mice (IAP ^Tg ) overexpressing human chimeric IAP. Objective: The aim of this study was to evaluate the effects of intestine-specific IAP overexpression on Western-type diet (WD)–induced atherosclerosis in Ldlr ^{−/ −} mice. Methods and Results: IAP ^Tg mice crossed into Ldlr ^−/− background (Ldlr ^−/− IAP ^Tg ) and Ldlr ^−/− littermates were fed WD for 16 weeks. Intestinal barrier dysfunction was assessed by monitoring plasma LPS levels and histological examination of colon. Overexpression of IAP attenuated WD-induced disruption of the colonic mucous layer, reducing intestinal barrier dysfunction and plasma LPS levels. Significant reduction in body, liver, and adipose tissue weight was also seen in WD-fed Ldlr ^−/− IAP ^Tg mice. Plasma and hepatic lipids were also significantly reduced in WD-fed Ldlr ^−/− IAP ^Tg mice. Consistently, intestinal lipid absorption was attenuated in Ldlr ^−/− IAP ^Tg mice with reduced expression of apical lipid transporters (CD [cluster of differentiation] 36, FATP4 [fatty acid transport protein 4], and NPC1L1 [Niemann-Pick C-like protein 1]) and intracellular lipid transport proteins (FABP [fatty acid binding protein] 1/2 and SCP2 [sterol carrier protein-2]). Attenuation of WD-induced atherosclerosis in Ldlr ^−/− IAP ^Tg mice was demonstrated by significant reduction in arch and total aortic lesions as seen by enface analyses, as well as significantly reduced atherosclerotic lesions in the ascending aorta of these mice. Conclusions: IAP overexpression improves intestinal barrier function by maintaining the integrity of the mucin layer in WD-fed Ldlr ^−/− IAP ^Tg mice and attenuates intestinal lipid absorption. Thus, by limiting translocation of gut-derived LPS or reducing plasma lipids, overexpression of IAP attenuates development of WD-induced atherosclerosis.