INTRODUCTION: Accumulating evidence suggest that imbalanced macronutrient composition would increase the risk of chronic diseases. However, previous studies that predominantly focused on individual macronutrients often failed to thoroughly elucidate this complex association. OBJECTIVES: This study aimed to comprehensively analyze the relationship between macronutrient clusters and all-cause mortality. METHODS: The study included 26,615 adults aged 20-75 years from the National Health and Nutrition Examination Survey (NHANES) 1999-2018. A three-dimensional cube method was employed to categorize clusters of macronutrients intake. The association between dietary macronutrient clusters and all-cause mortality was investigated using Cox proportional hazards modeling and restricted cubic spline (RCS) analysis. RESULTS: Over a weighted median follow-up duration of 7.58 years, 3,998 deaths were recorded. After adjusting for potential confounders, compared with the reference Cluster CONCLUSIONS: This study employed a three-dimensional cube approach to categorize the human macronutrients intake into 24 clusters. Cluster