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Objective— Obesity is associated with insulin resistance, chronic low-grade inflammation, and atherosclerosis. Toll-like receptor 4 (TLR4) participates in the cross talk between inflammation and insulin resistance, being activated by both lipopolysaccharide and saturated fatty acids. The present study was undertaken to determine whether TLR4 deficiency has a protective role in inflammation, insulin resistance, and atherosclerosis induced by a diabetogenic diet. Methods and Results— TLR4 and low-density lipoprotein (LDL) receptor double knockout mice and LDL receptor–deficient mice were fed either a normal chow or a diabetogenic diet for 24 weeks. TLR4 and LDL receptor double knockout mice fed a diabetogenic diet showed improved plasma cholesterol and triglyceride levels but developed obesity, hyperinsulinemia, and glucose intolerance equivalent to obese LDL receptor–deficient mice. Adipocyte hypertrophy, macrophage accumulation, and local inflammation were not attenuated in intraabdominal adipose tissue in TLR4 and LDL receptor double knockout mice. However, TLR4 deficiency led to markedly decreased atherosclerosis in obese TLR4 and LDL receptor double knockout mice. Compensatory upregulation of TLR2 expression was observed both in obese TLR4-deficient mice and in palmitate-treated TLR4-silenced 3T3-L1 adipocytes. Conclusions— TLR4 deficiency decreases atherosclerosis without affecting obesity-induced inflammation and insulin resistance in LDL receptor–deficient mice. Alternative pathways may be responsible for adipose tissue macrophage infiltration and insulin resistance that occurs in obesity.