Background <p>C-reactive protein-triglyceride glucose index (CTI) combined with anthropometric indices serve as integrative markers of insulin resistance, inflammation, and visceral obesity, exerting a detrimental effect on prognosis. However, the prognostic significance of CTI-anthropometric indices in individuals with cardiovascular-kidney-liver-metabolic (CKLM) syndrome remains uncertain. This study was conducted to elucidate the relationships between the CTI-anthropometric indices and mortality risk in this population.</p> Methods <p>This study included 14,203 individuals with CKLM syndrome from the National Health and Nutrition Examination Survey (NHANES, 1999–2018). Kaplan–Meier curve analyses, Cox proportional hazards models, Fine-Gray competing risk models, and restricted cubic spline (RCS) models were performed to evaluate the relationships of CTI-anthropometric indices with cardiovascular mortality and all-cause mortality. Receiver operating characteristic (ROC) curves were used to compare the predictive performance of CTI-anthropometric indices. Subgroup and sensitivity analyses were conducted to verify the robustness of the results.</p> Results <p>During a median follow-up period of 11.42 years, there were 772 cardiovascular deaths and 2,424 all-cause deaths. Kaplan‒Meier curve analyses indicated the lowest survival rate in the highest quartile of CTI-anthropometric indices (Log-rank <i>p</i> &lt; 0.001). Multivariable Cox regression analyses revealed that CTI-anthropometric indices in the highest quartile were associated with an increased risk of cardiovascular mortality and all-cause mortality, compared with the lowest quartile. The Fine-Gray competing risk models also demonstrated that CTI-anthropometric indices were independently associated with cardiovascular mortality. The RCS results showed a linear or non-linear association of CTI-anthropometric indices with cardiovascular mortality and all-cause mortality. ROC curve analyses indicated that CTI-a body shape index (CTI-ABSI) exhibited preferred predictive performance for mortality risk at 1-, 5-, and 10-year time points compared to other CTI-anthropometric indices. Subgroup and sensitivity analyses confirmed the robustness of the results of CTI-ABSI.</p> Conclusion <p>Elevated CTI-anthropometric indices were independently associated with increased mortality risk in individuals with CKLM syndrome, with CTI-ABSI emerging as the preferred predictor of mortality risk. These findings provide an approach for enhancing risk discrimination and stratification in individuals with CKLM syndrome.</p> Clinical trial number <p>Not applicable.</p> Graphical Abstract <p></p>