Both triglyceride-glucose (TyG) index, as a surrogate marker of insulin resistance, and low-density lipoprotein cholesterol (LDL-C) are independent risk factors for long-term prognosis among patients with cardio-renal-metabolic (CRM) disease. However, the co-exposures of TyG index and LDL-C to mortality is unclear. The aim of this study is to investigate the joint effects and risk stratification of the TyG index and LDL-C on all-cause and cardiovascular mortality in CRM patients. We analyzed CRM patients from the National Health and Nutrition Examination Survey (NHANES) database (1999-2018), calculating TyG index as Ln[fasting triglyceride (mg/dL)×fasting glucose (mg/dL)/2] and using multivariable Cox regression models to assess the joint effects of TyG index and LDL-C on all-cause and cardiovascular mortality. The interaction between the TyG index and LDL-C to mortality was also evaluated. During a median follow-up of 7.6 years, 22.8% and 8.4% of patients died from all-cause and cardiovascular causes, respectively. Among patients with LDL-C <
2.6 mmol/L, no significant differences were observed in all-cause and cardiovascular mortality when comparing higher TyG index to the lowest tertile (T1). Specifically, the hazard ratio (HR) for all-cause mortality in the second (T2) and third tertiles (T3) were 0.81 (95% confidence interval(CI): 0.59-1.09) and 0.87 (95%CI: 0.62-1.22), respectively, with a P for trend of 0.468. For cardiovascular mortality, the HR for T2 and T3 compared to T1 were 0.80 (95%CI: 0.48-1.32) and 0.72 (95%CI: 0.45-1.15), respectively, with a P for trend of 0.173. However, elevated TyG index was related to markedly increased risk of all-cause and cardiovascular mortality in patients with LDL-C ≥ 2.6 mmol/L. Specifically, for all-cause mortality, HR for T2 and T3 compared to T1 were 1.01 (95%CI: 0.79-1.28) and 1.38 (95%CI: 1.07-1.79), respectively, with a P for trend of 0.009. For cardiovascular mortality, the HR was 1.09 (95% CI: 0.72-1.65) for T2 and 1.80 (95% CI: 1.18-2.75) for T3, with a P for trend of 0.005. Interactive analysis also demonstrated that a significant association of TyG index and LDL-C with the risk of all-cause (P for interaction = 0.011) and cardiovascular (P for interaction = 0.050) mortality was observed. The findings highlight that elevated TyG index can significantly increase the risk of all-cause and cardiovascular mortality only among CRM patients with LDL-C ≥ 2.6 mmol/L, but not among patients with LDL-C <
2.6 mmol/L.