AIMS: This study aimed to explore relationships between visit-to-visit lipid variability, coronary artery calcification (CAC), inflammation, and long-term mortality, which may be prognostically relevant. METHODS: This prospective cohort study included participants from the Multi-Ethnic Study of Atherosclerosis with available plasma low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides from all three initial exams who underwent computed tomography CAC quantification at the third (index) exam. Visit-to-visit variability (coefficient of variation) was calculated from all three initial exams. Outcomes included the index Agatston score, cardiovascular mortality, all-cause mortality, and high-sensitivity C-reactive protein (hsCRP). RESULTS: Altogether, 1515 participants were analysed. Higher HDL-C variability was associated with higher index Agatston score (quartile 4 [Q4
vs Q1] adjusted marginal effects 0.25 [0.02-0.48]), but not LDL-C, TC, and triglycerides variability. Over a 15.1-year median follow-up, higher HDL-C (Q4 vs Q1: adjusted sub-hazard ratio 2.68 [1.61-4.48]) and TC (Q4 vs Q1: adjusted sub-hazard ratio 2.13 [1.17-3.89]) variability, but not LDL-C and triglycerides variability, were associated with higher risk of cardiovascular mortality, which remained significant after adjusting for the index Agatston score. Additionally, higher HDL-C variability was associated with higher risk of all-cause mortality (Q4 vs Q1: adjusted hazard ratio 1.46 [1.00-2.11]), but LDL-C, TC, and triglycerides variability were not. HDL-C (Q4 vs Q1: adjusted β: 0.132 [0.034-0.230]) and TC (Q4 vs Q1: adjusted β: 0.210 [0.064-0.357]) variability, but not LDL-C and triglycerides variability, may be correlated with hsCRP. CONCLUSIONS: Elevated HDL-C variability was associated with greater CAC burden and long-term risks of cardiovascular and all-cause mortality. These mortality-related associations were probably not completely explainable by atherosclerosis.