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.