Objective To explore the phenotypic differences and pathological mechanisms of insulin resistanceand atherosclerosis (IR-AS) in white hair black eye (WHBE) rabbits and Japanese white (JW) rabbits. Methods Twelve JW rabbits and 12 WHBE rabbits were randomly divided into the normal control group (NC) and high fat and sugardiet (HF) group with six rabbits in each group. The IR-AS model was induced by feeding a high fat and sugar diet for 12weeks. At the end of modeling, blood samples were collected to determine blood lipid, superoxide dismutase (SOD), andmalondialdehyde (MDA) levels. A glucose tolerance test was conducted, and the area under the curves of blood glucoseand insulin was calculated. mRNA expression of microsomal triglyceride transfer protein (MTTP), nuclear factor-like 2(Nrf2), and SOD1 genes in the liver was detected, pathological changes in fat tissues and aortic wall by HE staining, andCD68 expression in aortic tissues were observed. Results Compared with the NC group, HF rabbits showed significantobesity, hyperlipidemia, glucose intolerance, hyperinsulinemia, and increased HOMA-IR. Moreover, HF rabbits exhibiteddecreased SOD activity and increased MDA contents in their plasma and liver, increased mRNA expression of MTTP andNrf2 in the liver tissue, and decreased mRNA expression of SOD1. In addition, vascular lipid deposition, AS plaque size,and CD68 expression were increased significantly. Compared with the JWHF group, TG, LDL-C, HOMA-IR, U_GLU,MDA content, fat diameter, SOD1, AS lesion degree, and vascular CD68 expression in the WBHF group were significantlydifferent. Conclusions A high-fat and sugar diet induces the formation of IR-AS in rabbits, resultsing in an obvious lipidmetabolism impairment, inflammatory and AS lesions. However, the degree of pathological changes in WHBE rabbits issignificantly more serious than that in JW rabbits, which may be related to the differences in lipid metabolism and the oxidative stress response between the two rabbit strains.