ABSTRACT Coronary artery calcium (CAC) provides predictive information for risk of coronary heart disease (CHD) events beyond that gained from traditional cardiovascular disease (CVD) risk factors. Hispanics/Latinos have lower prevalence of CAC than whites, even after accounting for differences in CVD risk factors. They also have lower rates of CVD mortality and longer life expectancies despite higher rates of risk factors and adverse socioeconomic conditions (the ‘Hispanic Paradox’), lending credence to the existence of Hispanic/Latino-specific CVD protective mechanisms. Little data currently exist on the presence/absence and extent of CAC and CT- derived plaque volume, density, and distribution in diverse Hispanics/Latinos, and their associations with sociocultural characteristics and lifestyle factors that have been associated with CVD in the Hispanic Community Health Study/ Study of Latinos (HCHS/SOL) and other cohorts. Another critical knowledge gap is whether epigenetic mechanisms, i.e., DNA methylation, alone or in conjunction with genetic factors, act as an important biological link between such risk or protective factors and subclinical/clinical CVD in Hispanics/Latinos. The proposed study aims to generate critical data on subclinical coronary atherosclerosis (CAC and CT-derived plaque volume, density, and distribution) for Hispanic/Latino adults from all major heritage groups in the US (Mexican, Puerto Rican, Cuban, Dominican, and Central/South American) and examine relationships with sociocultural factors, lifestyle factors, traditional CVD risk factors, and epigenomic patterns. This study will be conducted ancillary to the ongoing HCHS/SOL, which examined 16,415 Hispanic/Latino men and women ages 18-74 years at Visit 1 (2008-2011) from 4 US communities (San Diego, CA; Chicago, IL; Bronx, NY; and Miami, FL) and 11,623 participants (81.4% follow-up rate) at Visit 2 (2014-2017). The proposed study will capitalize on available HCHS/SOL data and will assess CAC absence/presence and features in conjunction with ongoing HCHS/SOL Visit 3 (2020-2023) in 4,109 participants ages >45 years (mean age 60.5 years, an optimal time window for CAC detection) and free of known history of CVD. Longitudinal examination of epigenetic biomarkers will be conducted using stored blood DNA samples from HCHS/SOL Visits 1 and 2 for a subset of participants (50% of participants who undergo scanning, n=2,054). The proposed study will address critical knowledge gaps in a highly cost-effective manner by capitalizing on the established HCHS/SOL infrastructure. Examination of these factors in this heterogeneous, well-characterized cohort, has the potential to generate novel and insightful epidemiological, etiologic, and mechanistic information beyond that gained from previous studies, which can help to identify novel preventive targets and inform development of precision prevention/treatment strategies that may benefit all racial/ethnic groups.