Background <p>To investigate the associations of systemic inflammation, lipid metabolism, bone metabolism markers, and muscle quality with thoracic aortic calcification (TAC) in patients undergoing maintenance dialysis.</p> Methods <p>This multicenter cross-sectional research involved 1916 patients aged 18–80 years who underwent maintenance dialysis across four tertiary hospitals in China between January 2020 and June 2023. Non-contrast chest CT scans were performed to assess TAC and skeletal muscle density (SMD). Associations of TAC with SMD, monocyte-lymphocyte ratio (MLR), and high-density lipoprotein (HDL), apolipoprotein (apo) A1, alkaline phosphatase (ALP) were explored via multivariate regression models. Stratified analysis was further done to investigate the effect of SMD on TAC. Mediation analyses were conducted to identify the mediators.</p> Results <p>Multivariate linear regression analysis demonstrated significant positive associations between TAC and MLR (β = 0.43; 95%CI: 0.09, 0.78) and ALP (2.24; 0.89, 3.58), and negatively with SMD (-0.05; -0.07, -0.03), HDL (-1.01; -1.51, -0.51) and apo A1 (-1.13; -1.72, -0.55). The relationship between SMD and TAC was not affected by age, sex, smoking status, dialysis modality, dialysis vintage, coronary heart disease, or hyperlipidemia. The mediation effects of SMD were 8.73%, 6.42%, 8.74%, and 13.26% on the associations of TAC with MLR (95%CI: 0.014, 0.263), ALP (0.011, 0.230), HDL (0.032, 0.217) and apo A1 (0.052, 0.317) respectively. When TAC is treated as a binary variable, the results of the multivariable logistic regression and mediation analysis remain consistent.</p> Conclusions <p>This study highlights the complex interplay of MLR, ALP, HDL, apo A1 and SMD with TAC in patients undergoing maintenance dialysis. Improving skeletal muscle density may represent a novel strategy to mitigate the likelihood of TAC.</p>