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OBJECTIVE: The purpose of this cross-sectional study was to examine the association between elevated depressive symptoms and the clinical severity of sickle cell disease (SCD) using African-American adults with and without SCD. STUDY DESIGN: The population consisted of 102 African-American adults with SCD, diagnosed using hemoglobin electrophoresis, individually matched on age (+/-5 years), gender and recruitment location to 103 African-American adults without SCD (mean age of all subjects was 35.4 years, 55.6% female). Logistic regression was used to examine the association between SCD clinical severity and elevated depressive symptoms in bivariate and multivariable analyses. RESULTS: The prevalence of elevated depressive symptoms as measured using the 10-item Center for Epidemiological Studies Depression Scale (CES-D) was 38.6% in those with SCD, compared to 27.5% in those without SCD; however, this difference was not statistically significant (p>0.05). Compared to African Americans without SCD, African Americans with SCD were less educated, had lower incomes, and were more likely to be unemployed or disabled (p<0.01). The odds of having elevated depressive symptoms were 1.78 (CI: 0.94, 3.38) for those with high clinical SCD severity compared to those without SCD in bivariate analysis and 1.37 (CI: 0.62, 3.02) in multivariable analysis after adjusting for socioeconomic factors. CONCLUSIONS: The reported relationship between elevated depressive symptoms and SCD may be a result of the adverse economic conditions associated with SCD.