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Factors contributing to racial differences in health care system distrust (HCSD) are currently unknown. Proposed potential contributing factors are prior experiences of racial discrimination and racial residential segregation.Random digit dialing survey of 762 African American and 1267 white adults living in 40 US metropolitan statistical areas. Measures included the Revised Health Care System Distrust scale, the Experiences of Discrimination scale, metrics of access to care, sociodemographic characteristics, and the level of racial residential segregation in the city (using the isolation index).In unadjusted analyses, African Americans had higher levels of HCSD, particularly values distrust, and greater experiences of discrimination. Experience of discrimination was also strongly associated with HCSD. Adjusting for sociodemographic characteristics, health care access, and residential segregation had little effect on the association between African American race and overall HCSD or values distrust. In contrast, adjusting for experiences of racial discrimination reversed the association so that distrust was lower among African Americans than whites (odds ratio 0.53; 95% confidence interval, 0.33–0.85 for the overall measure). The Sobel test for mediation was strongly significant (P<0.001).Higher HCSD among African Americans is explained by a greater burden of experiences of racial discrimination than whites. Reasons for higher distrust among whites after adjusting for experiences of racial discrimination are not known. Efforts to eliminate racial discrimination and restore trust given prior discrimination are needed.