BackgroundGallstone disease is a condition affecting the digestive system, strongly linked to inflammation and lipid metabolism. Inflammatory markers derived from high-density lipoprotein (HDL), incorporating both immune cells and HDL-C, play a crucial role in assessing inflammatory responses. This study aims to explore the relationship between these HDL-related inflammatory indices and gallstone disease.MethodsThe study population was derived from the National Health and Nutrition Examination Survey (NHANES) 2017-2020 and 2021-2023 datasets. To assess the association between HDL-related inflammatory indices and gallstone disease, weighted multivariable logistic regression and restricted cubic spline (RCS) analysis were utilized. Additionally, subgroup analysis was conducted to confirm the consistency of the results across different subpopulations.ResultsAmong the 16,871 participants included in the study, 11.0% were diagnosed with gallstone disease. When compared to the lowest quartile, those in the highest quartile of lymphocyte-to-HDL cholesterol ratio (LHR), monocyte-to-HDL cholesterol ratio (MHR), neutrophil-to-HDL cholesterol ratio (NHR), and platelet-to-HDL cholesterol ratio (PHR) faced an elevated risk of gallstone disease by 58.6% (OR = 1.586, 95% CI: 1.143-2.2), 67.6% (OR = 1.676, 95% CI: 1.275-2.204), 68.7% (OR = 1.687, 95% CI: 1.244-2.287), and 42.7% (OR = 1.427, 95% CI: 1.101-1.849), respectively. The correlation between HDL-related inflammatory indices and gallstone disease was more pronounced in females, individuals without diabetes or hypertension, nonsmokers, and those who consumed alcohol.ConclusionsThis research identified a positive correlation between HDL-related inflammatory indices and gallstone disease in a nationally representative sample. These indices can be derived from routine blood tests at no additional cost, making them practical and cost-effective tools for early risk stratification and potential large-scale screening.