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Background: Although HDL-C is inversely associated with cardiovascular risk, no causal relationship has been demonstrated. Since HDL comprises a group of heterogeneous subfractions, they might have different effects on atherosclerosis, and its effects may be modified by the presence of diabetes mellitus.Hypothesis: HDL-C subfractions exert different effects on subclinical carotid atherosclerosis, and diabetes modifies these effects.Methods: We evaluated 3,930 individuals between 35 and 74 years (45.6% men) without previous cardiovascular disease not using lipid-lowering drugs. HDL2-C and HDL3-C were obtained by zonal ultracentrifugation. The relationships between each HDL-C subfraction and cIMT were analyzed by multiple linear regression models.Results: The mean cIMT was 0.796±0.195 mm, the mean total HDL-C was 55.1±14.4 mg/dl, HDL2-C was 14.9±6.7, and HDL3 was 40.1±8.4 mg/dl. Total HDL-C and subfractions, as well as HDL2-C/HDL3-C ratio were negatively associated with cIMT after adjustment for race/ethnicity, age, and sex (all p<0.001) and further for smoking status, alcohol use, physical activity, LDL-C, systolic blood pressure, waist circumference, fasting serum glucose, body mass index, triglycerides and antihypertensive use (HDL-C: p = 0.003, HDL2-C: p = 0.01; HDL3-C: p = 0.003; HDL2-C/HDL3-C ratio: p = 0.02). When stratified by diabetes status, both HDL2-C (p=0.03) and HDL2-C/HDL3-C ratio (p= 0.01) showed a negative association with cIMT in people with diabetes (n=531) after adjusting for confounding variables. These associations were not observed in individuals without diabetes (p = 0.11 and p = 0.30, respectively).Conclusion: HDL2-C and HDL3-C subfractions, as well as the HDL2/HDL3-C ratio, are inversely associated with cIMT after adjustment for traditional risk factors. This association of HDL2-C/HDL3-C ratio and HDL2-C is modified by the presence of diabetes, where it is more pronounced.