The U.S. Latinos carries a disproportionate burden of Metabolic Syndrome (MetS) and Subclinical Atherosclerosis (ATS), therefore identifying the contribution of psychological factors to both risk for MetS and subclinical ATS is relevant. Two studies were conducted with the U.S. resident Latinos enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). Study 1 investigated the longitudinal associations of negative affect (i.e. depressive symptoms, anger, and anxiety trait), and psychosocial stress (i.e. chronic stress, and both daily and lifetime experiences of discrimination) with severity of MetS (indexed by the number of MetS criteria), and mediators and moderators of these associations. Study 2 investigated the longitudinal associations between psychological factors, and ATS indexed by coronary calcium calcification, intima-media thickness, artery plaque, common carotid artery-internal carotid artery, and related mechanisms. Study 1 was conducted with Mexican Americans (n=801), Dominican American (n=175), Puerto Rican American (n=202), and other Central/South Americans (n=213), whereas Study 2 only studied Mexican American participants (n= 801). Study 1 revealed that Mexican-Americans evidenced greater severity of MetS, the highest levels of fasting glucose and triglycerides, the largest waist size circumference, and the lowest HDL cholesterol levels over time than the other U.S. Latinos. Psychological stress and negative affect were associated with MetS severity in males only, and men evidenced an indirect effect of physical activity on MetS severity via inflammation. Study 2 demonstrated that neither negative affect nor psychological stresses were related to ATS. Several mediators were significant, with physical activity mediating the effect of chronic stress and negative affect on MetS severity. Furthermore, physical activity and inflammation as a sequence mediated the association of psychological factors and MetS severity. These studies suggest a different epidemiological health profile for U.S. Latinos, with Mexican-Americans in the region studied having a greater MetS severity across 10 years of follow-up. Furthermore, gender moderated the potential contribution of psychological factors to MetS severity, and physical activity and inflammation mediated the associations of psychological factors with MetS in Mexican-Americans participants. This research adds to our understanding of within group differences in health among Latinos, as well as the contribution of psychological factors to MetS and ATS and related cardio-metabolic mechanisms.