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Recent data suggest that visit-to-visit variability of cholesterol is associated with cardiovascular events. We evaluated the role of lipid variability as a determinant of end-stage renal disease (ESRD).Using nationally representative data from the Korean National Health Insurance System, 8 493 277 subjects who were free of ESRD and who underwent ≥3 health examinations during 2005 to 2010 were followed to the end of 2015. Total cholesterol (TC) variability was measured using the coefficient of variation, SD, and the variability independent of the mean. The primary outcome was the development of ESRD, defined as a combination of the relevant disease code and the initiation of renal replacement therapy. There were 11 247 cases of ESRD during a median follow-up of 6.1 years. There was a graded association between a higher TC variability and incident ESRD. In the multivariable adjusted model, the hazard ratios and 95% confidence intervals comparing the highest versus lowest quartiles of coefficient of variation of TC were 2.66 (95% confidence interval, 2.52–2.82). The results were consistent when the variability of TC was modeled using SD and variability independent of the mean and were independent of preexisting chronic kidney disease.Increasing TC variability was associated with an increasing incidence of ESRD.