Background/Aims: The study aimed to investigate the interactions of genetic variants in the leptin receptor (LEPR) gene with lipid profile changes following a high-carbohydrate/low-fat (HC/LF) diet in a Chinese Han population. Methods: Fifty-six healthy young subjects were given washout diets, followed by HC/LF diets consisting of 15% fat and 70% carbohydrate for 6 days. Serum lipid profiles and insulin levels before and after HC/LF diets were analyzed. Results: Statistically elevated high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apoA-I), and insulin levels were only observed in the GG genotype of LEPR Lys109Arg but not in the A carriers after HC/LF diet. When gender was taken into account, significantly increased HDL-C, apoA-I, and insulin levels were found in women with the GG genotype. Moreover, lower low-density lipoprotein cholesterol (LDL-C) and higher insulin levels were only observed in subjects with the GG genotype of LEPR Gln223Arg, while higher HDL-C and apoA-I were only found in the A allele carriers. Additionally, the lower LDL-C and body mass index (BMI), and higher HDL-C and insulin levels were only observed in subjects with the GG genotype of LEPR Lys656Asn. Conclusions:LEPR polymorphisms contribute to the heterogeneities in BMI, LDL-C, and HDL-C responsiveness that are induced by a HC/LF diet in healthy young Chinese adults.