Introduction: Social determinants of health (SDOH) are key for the identification of populations at increased risk of developing cardiovascular risk factors (RFs) and ASCVD. In contrast, whether at the individual level SDOH improve current ASCVD risk prediction paradigms beyond traditional RFs and CAC, is unknown. Also, while CAC predicts outcomes across a wide range of risk profiles, its performance across groups with increasing levels of social vulnerability has not been evaluated. Methods: MESA is a prospective study of US adults free of clinical ASCVD at baseline. We developed an SDOH index inclusive of 14 determinants from 5 domains. The index ranged 0-1 and was divided into quartiles, with higher ones representing worse SDOH. Cox regression was used to evaluate the adjusted associations between CAC, SDOH, their interplay, and ASCVD events; and C-statistics were used to assess improvement in risk discrimination for prediction of all/hard events with CAC, SDOH, and both. Results: We included 6,479 MESA participants (50% with CAC=0, 24% CAC>100). The incidence of hard ASCVD events was higher for increasing CAC scores across all SDOH quartiles ( Figure Panel A ). The lowest incidence was noted in those with CAC=0 and favorable SDOH (2/1000 person-ys) and highest in those with CAC>100 and most unfavorable SDOH (20.6/1000 person-ys). CAC improved the discriminatory ability of prediction models, while improvements with SDOH were smaller and were none on top of CAC ( Panel B ). Results were consistent in analyses that evaluated education and income as SDOH exposures. Conclusion: CAC stratifies ASCVD risk across the spectrum of social vulnerability and can guide personalized risk management also among most socially vulnerable populations. In contrast, SDOH fail to improve risk prediction beyond traditional RFs and CAC. Our results provide further support to current ASCVD risk assessment paradigms in the US, and suggest that SDOH have a limited role in this specific setting.