This cohort of "late middle-aged" African Americans has an excess of disability. We aimed to determine associations of circulating cytokine receptors (sTNFR1, sTNFR2, and sIL-6R) and C-reactive protein (CRP) with disability, physical function, and body composition. Stratified sampling of two socioeconomically diverse strata of St Louis, Missouri, occurred in 2000-2001. Inclusion criteria were self-reported black or African American race, born 1936-1950 inclusive, and Mini-Mental State Examination score of 16 or greater. In-home evaluations of handgrip strength, lean body mass percentage (LBM%), physical performance, upper and lower body functional limitations (UBFLs and LBFLs), and basic and instrumental activities of daily living (BADLs and IADLs) were collected. Of the 998 participants, 368 had blood sampled at baseline. Serum was stored and assayed in 2006. Absolute risks were LBFLs of 2 or more, 46%; UBFLs of 1 or more, 23.5%; BADLs of 2 or more, 20.6%; and IADLs of 2 or more, 22.5%. Independent of age, sex, and underlying comorbid conditions, higher CRP and sTNFR were associated with poorer physical performance (beta = -1.462, p < .001 and beta = -0.618, p = .003), UBFLs (odds ratio [OR] 2.26, 95% confidence interval [CI] 1.1-4.64 and OR 1.39, 95% CI 0.96-2.02), LBFLs (OR 2.30, 95% CI 1.19-4.45 and OR 1.91, 95% CI 1.26-2.91), BADLs (OR 2.79, 95% CI 1.03-5.96 and OR 1.66, 95% CI 1.11-2.46), and IADLs (OR 2.13, 95% CI 1.03-4.41 and OR 1.43, 95% CI 0.99-2.08). Higher CRP (beta = -3.251, p <.001), sIL-6R (beta = -6.152, p = .013), and lower adiponectin (beta = 2.947, p = .052) were associated with lower LBM%. Higher CRP and sTNFR are independently associated with disability and physical dysfunction. Higher sIL-6R, CRP, and lower adiponectin associate with lower LBM%.