BACKGROUND AND AIMS: Patients with metabolic dysfunction-associated steatotic liver disease (MASLD) often manifest a combination of cardiometabolic risk factors of varying severity. The cardiometabolic phenotypes and their associations with advanced liver fibrosis and all-cause mortality among patients with MASLD warrant further investigation. METHODS AND RESULTS: A total of 4209 and 1901 eligible participants were obtained from the National Health and Nutrition Examination Survey and included in the original and replication datasets, respectively. In the original dataset, three distinct and stable cardiometabolic phenotypes were identified using unsupervised cluster analyses, including mild cardiometabolic risk factor (MCMRF) phenotype, overweight combined with high diastolic blood pressure dominated (OCHBP) phenotype, and severe glucose and lipid metabolic dysfunction dominated (SGLMD) phenotype. The above phenotypes were subsequently replicated in the replication dataset, demonstrating similar characteristics. After adjusting for potential covariates, the results of logistic and Cox regression models showed that OCHBP and SGLMD phenotypes were significantly associated with higher odds of advanced liver fibrosis (OCHBP: OR = 4.37, 95 % CI: 1.54-12.35, P = 0.020
SGLMD: OR = 9.66, 95 % CI: 4.76-19.61, P = 0.002) and an increased risk of all-cause mortality (OCHBP: HR = 1.39, 95 % CI: 1.17-1.65, P <
0.002
SGLMD: HR = 2.51, 95 % CI: 1.86-3.40, P <
0.002) compared to the MCMRF phenotype. Moreover, the observed associations remained statistically significant in most subgroups, and a series of sensitivity analyses further confirmed the robustness of these findings. CONCLUSION: Three heterogeneous cardiometabolic phenotypes were identified among participants with MASLD, showing significant associations with two critical outcomes. These novel phenotypes may be of great importance to precision medicine in MASLD.