<p><b>BACKGROUND: </b>U.S. Hispanics/Latinos experience high lifetime risk for Type 2 diabetes and concurrent psychological depression. This comorbidity is associated with poorer self-management, worse disease outcomes, and higher mortality. Syndemic theory is a novel social epidemiological framework that emphasizes the role of economic and social adversity in promoting disease comorbidity and health disparities.</p><p><b>PURPOSE: </b>Informed by the syndemic framework, this study explored associations of socioeconomic and psychosocial adversity (low income/education, trauma history, adverse childhood experiences, ethnic discrimination, neighborhood problems [e.g., violence]) with comorbidity of diabetes and depression symptoms in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) and Sociocultural Ancillary Study.</p><p><b>METHODS: </b>Participants were 5,247 Latino adults, aged 18-74, enrolled in four U.S. cities from 2008 to 2011. Participants completed a baseline physical exam and measures of depression symptoms and psychosocial adversity. Multinomial logistic regression analyses were conducted to examine associations of adversity variables with comorbid diabetes and high depression symptoms.</p><p><b>RESULTS: </b>Household income below $30,000/year was associated with higher odds of diabetes/depression comorbidity (odds ratio [OR] = 4.61; 95% confidence interval [CI]: 2.89, 7.33) compared to having neither condition, as was each standard deviation increase in adverse childhood experiences (OR = 1.41; 95% CI: 1.16, 1.71), ethnic discrimination (OR = 1.23; 95% CI: 1.01, 1.50), and neighborhood problems (OR = 1.53; 95% CI: 1.30, 1.80).</p><p><b>CONCLUSION: </b>Low household income, adverse childhood experiences, ethnic discrimination, and neighborhood problems are related to comorbid diabetes and depression in U.S. Latinos. Future studies should explore these relationships longitudinally.</p>