Background: South Asians (SA) are the second largest US immigrant group and have excess cardiometabolic (CM) disease. While acculturation is associated with increased CM risk among immigrants and refugees, the role of acculturation on SA CM risk is relatively unknown. CM disease presents as a syndemic or synergistic epidemic involving multiple disease clusters as well as the biological, social, and psychological interactions from the acculturative process to worsen morbidity within subgroups. Methods: We used latent class analysis to identify SA CM risk based on acculturation subgroups using data from adults aged 40-84 in the Mediators of Atherosclerosis in South Asians Living in America study (N=771). The distal outcome of CM risk was constructed using hypertension, type 2 diabetes, and body mass index. Proxies of acculturation included years lived in the US, English proficiency, cuisine eaten at home, cultural traditions, ethnicity of friends, social and neighborhood support, and experienced discrimination; as well as mental health indicators, which included depression, trait anxiety, anger, and positive and negative spiritual coping. Covariates included demographic characteristics, family income, education, study site, exercise, smoking, alcohol use, religiosity and spirituality. Results: Four CM risk profiles and acculturation subgroups were identified: 1) lowest risk [73.8%] were the most integrated with both SA and US culture; 2) intermediate-low risk [13.4%] had high mental health distress and discrimination and separated from SA and US culture; 3) intermediate-high risk [8.9%] were more assimilated with US culture; and 4) highest risk [3.9%] were more assimilated with US culture [Figure]. Conclusion: Our approach identified distinct nuanced profiles of syndemic CM risk to understand how acculturation and sociocultural factors cluster with health in US South Asians. Our syndemic framework will further understanding of CM risk among SA to best design tailored prevention and intervention programs.