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Disparities exist in the recognition and treatment of depression among Hispanics in the United States, creating a social, ethical, economic, and public health burden. This study was designed to generate an improved understanding of the causes of and/or contributors to depression within this population. It was specifically designed to 1) assess the prevalence and severity of depression among Hispanic adults in the United States relative to adults of other race/ethnicities in the United States; 2) clarify the inconsistent results in the literature concerning the relationship between acculturation and depression among Hispanic adults in the United States; and 3) fill a gap in the literature by evaluating the potential for inflammation to mediate the relationship between acculturation and depression among Hispanic adults in the United States. The biopsychosocial model was used as a theoretical foundation for this study. Data from the 2009-2010 National Health and Nutrition Examination Survey were analyzed descriptively and via logistic regression. Findings confirmed higher prevalence of depression among Hispanic adults compared with non-Hispanic White adults, and that a lower degree of acculturation was consistently associated with a decreased likelihood of depression among Hispanics. No mediating effect of inflammation on the relationship between acculturation and depression was observed. The findings from this study are intended for use by health care providers, health educators, and public health practitioners to improve depression prevention, diagnosis, and treatment opportunities within this population and to accordingly to affect positive social change.