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This cross-sectional study examined the bio-behavioral pathways that may account for poorer self-rated health (SRH) among Mexican American immigrants compared to non-Hispanic whites in the U.S. The association between acculturation and SRH among Mexican American immigrants was also examined. The 2009-2010 National Health and Nutrition Examination Survey enrolled 592 Mexican American immigrants and 2391 U.S.-born, non-Hispanic whites. Predictor variables included Mexican American ethnicity and a validated Acculturation Index comprised of language spoken at home, interview language, and proportion of life residing in the U.S. The mediator variables were depressive symptoms and log10 transformed C-reactive protein. Compared to U.S.-born, non-Hispanic whites, Mexican American immigrants reported poorer SRH. Mexican American immigrant status was also indirectly associated with worse SRH via greater C- reactive protein. Among Mexican American immigrants, greater acculturation was associated with better SRH. Poorer SRH among Mexican American immigrants may be partially attributable to greater inflammation. However, Mexican American immigrants with higher levels of acculturation report better SRH.