Brominated flame retardants (BFRs) are a widely used category of environmentally persistent, bioaccumulative chemicals. However, research focusing on the potential adverse effects of these chemicals on human health, particularly on cardiovascular issues, remains limited. This study aimed to investigate the association between BFR exposure and the development of atherosclerosis with a particular focus on the potential role of inflammatory indicators as mediators. Six typical BFRs (BB-153, BDE-28, BDE-47, BDE-99, BDE-100, and BDE-153) and six inflammatory indicators (white blood cells [WBC], neutrophils, mononuclear cells, lymphocytes, blood platelet [PLT], and C-reactive protein) were examined using data from 1654 participants in the National Health and Nutrition Examination Survey 2003-2004. Statistical analysis revealed that the levels of serum BFR, including BB-153, BDE-28, BDE-47, BDE-99, and BDE-100, were markedly elevated in the atherosclerosis group compared with those in the non-atherosclerosis group (all P <
0.05). Restricted cubic splines demonstrated a nonlinear relationship between BB-153 and BDE-100 and atherosclerosis, with BB-153 exhibiting a significant correlation with atherosclerosis in an inverted U-shape (P = 0.001). In the Binary logistic regression model, BB-153, BDE-28, BDE-47, and BDE-100 were significantly correlated with atherosclerosis, with BB-153 exhibiting the strongest association [OR = 2.059, 95 % CI: (1.540-2.754), P = 0.001]. BFRs were re-analyzed after being divided into four quartiles, revealing a dose-response relationship in which the risk of atherosclerosis increased with higher serum BFRs levels. Bayesian kernel machine regression model and quantile-based G-computation model analyses also demonstrated consistent correlations with mixed BFR exposures, with BB-153 having the greatest contribution. Moreover, mediation analysis demonstrated that WBC count and PLT levels were the primary mediators (proportion mediated: 5.10 % and 4.20 %, respectively) in the link between of BDE-153, BDE-100, and atherosclerosis. Thus, the inflammatory status may serve as a mediating factor in the relationship between BFR exposure and atherosclerosis.