Introduction: This study investigates social determinants of systemic inflammation, focusing on race, SES, and perceived discrimination. Methods: Data on 884 white and 170 black participants were obtained from the Survey of Midlife in the U.S., a cross-sectional observational study combining survey measures, anthropometry, and biomarker assay. Data, collected in 2004-2009, were analyzed in 2016. Main outcome measures were fasting blood concentrations of C-reactive protein, interleukin 6, fibrinogen, and E-selectin. For each biomarker, series of multivariate linear regression models were estimated for the pooled sample and separately for blacks and whites. Full models included social determinants; psychological, lifestyle, and health factors; and demographic covariates. Results: Bivariate analyses indicated higher concentrations of all inflammation markers among blacks compared with whites (p < 0.001). In fully adjusted models using the pooled sample, racial differences persisted for interleukin 6 (p < 0.001) and fibrinogen (p < 0.01). For E-selectin and C-reactive protein, racial differences were explained after adjusting for covariates. Education was linked to lower fibrinogen concentration (p < 0.05) in the fully adjusted model and C-reactive protein concentration (p < 0.01) after adjusting for demographic factors and income. Lifetime perceived discrimination was related to higher concentrations of fibrinogen (p < 0.05) in the fully adjusted model, and higher concentrations of E-selectin and interleukin 6 (p < 0.05) after adjusting for socioeconomic status (SES) and demographic factors. Conclusions: This study clarifies the contributions of race, SES, and perceived discrimination to inflammation. It suggests that inflammation-reducing interventions should focus on blacks and individuals facing socioeconomic disadvantages, especially low education.