BACKGROUND: Increased carotid intima-media thickness is associated with higher cardiovascular disease risk. This study aimed to evaluate the contributions of cardiovascular risk factors and inheritance to segment-specific carotid intima-media thickness. DESIGN: Cross-sectional observational study. METHODS: A total of 706 Korean adults was selected from the Healthy Twin Study. The intima-media thickness of common, carotid bifurcation, and internal carotid artery were measured using B-mode ultrasound. Behavioral and biological cardiovascular risk factors were measured. Quantitative genetic and linear mixed analyses were performed to examine inherited and environmental contributions to intima-media thickness variation. RESULTS: Heritability of intima-media thickness was moderately high with estimates (95% confidence intervals) of 0.48 (0.37, 0.59), 0.38(0.27, 0.49), and 0.45(0.34, 0.55) for common, carotid bifurcation, and internal carotid artery, respectively. The additive genetic cross-trait correlations between the segments ranged between 0.43 and 0.75, suggesting a shared genetic influence on the three carotid segments. Additive inherited effects contributed 21% and 31% (common and internal carotid, respectively) to the total variance of the intima-media thickness, while measured cardiovascular risk factors accounted for 46% and 26% (common and internal carotid, respectively). The cardiovascular risk factors significantly associated with carotid intima-media thickness were as follows: in men, alcohol use (bifurcation); physical activity (common and internal); BMI (all segments); diabetes (bifurcation and internal); hypertension (internal); and HDL-cholesterol (common and bifurcation); and in women, smoking (bifurcation), hypertension (common), total and LDL cholesterol (bifurcation and internal), and hs-CRP (common and internal). CONCLUSIONS: Individual cardiovascular risk factors were differentially associated with carotid intima-media thickness by segments and sex. Inherited effects made a heterogeneous contribution to intima-media thickness by segment. These findings may explain the differences in cardiovascular disease occurrence between men and women.