Background: The volume of intrathoracic fat has been associated in some studies with cardiovascular diseases risk factors. To further assess the role of intrathoracic fat in coronary atherosclerosis risk, we measured the volume of intrathoracic fat in 910 relatively healthy Amish adults from Lancaster County, PA, and assessed correlations of intrathoracic fat volume and its two subcomponents with cardiovascular risk factors and coronary artery calcification (CAC). Further we also explored the heritability and genetic determinants of intrathoracic fat volume. Methods and results: Intrathoracic fat, epicardial and pericardial fat volume were measured from EBCT scans (3-mm thickness) obtained from the right pulmonary artery to the diaphragm. There was high correlation between epicardial, pericardial and intrathoracic fat volume. Similar findings were observed while examine intrathoracic, epicardial and pericardial fat volume. Epicardial fat volume was significantly correlated with older age (p<0.001), male gender (p<0.01), and increasing BMI (p<0.001). Multivariate regression model was used to evaluate the correlation between epicardial fat volume and cardiovascular disease risk factors while adjusting for age, gender, family structure and BMI. Epicardial fat volume was associated with higher systolic (p<0.01) and diastolic (p=0.04) blood pressure, higher pulse pressure (p=0.02), higher levels of fasting glucose, insulin, triglycerides (p<0.001) and total cholesterol (p=0.05). After adjusting for BMI or waist circumference, the above associations were diminished and no longer statistically significant. Neither coronary calcification score nor coronary calcification presence (coronary calcification score>0) was associated with increased epicardial fat volume after adjusting for age and gender. Similar associations were found examining pericardial and intrathoracic fat volume. Genetic analysis revealed that intrathoracic fat shares both environmental and genetic determinants with other obesity traits. Our genome wide association analysis and targeted SNPs analysis identified several candidate SNPs/genes which might be specifically associated with this regional fat deposit. Conclusions: We conclude that intrathoracic fat volume is significantly correlated with adverse cardiovascular risk factors (although not with increased CAC) in age and gender adjusted models. However, the associations were not independent of BMI. Intrathoracic fat volume closely correlates with various obesity measurements, except liver fat, by sharing both similar environmental and genetic influences.