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• A large SUA variation was associated with a higher risk of CVD and its subtypes. • Both a large rise or fall in SUA was associated with a higher risk of CVD. • The harmful effect of a large variation of SUA on CVD was more pronounced in older adults than that in young adults. • The hazardous effect of SUA variation on CVD was mainly induced by excessive inflammation and elevated blood pressure. The association of serum uric acid (SUA) with cardiovascular disease (CVD) is inconsistent and limited by a single measurement of SUA. This study aimed to investigate the association of SUA variation, considering its magnitude and direction, with the risk of CVD. This study included 41,578 participants with four biennial measurements of SUA during 2006–2012 from the Kailuan study. SUA variation was measured using the coefficient of variation (primary index), standard deviation, average real variability, and variability independent of mean, and the direction of variation was also assessed. Multivariate-adjusted Cox regressions were used to assess the associations, and Bayesian network was utilized to find the most important pathway from SUA variation to CVD. During a median follow-up of 6.74 (interquartile range: 6.45–7.03) years, we identified 1,852 (4.45%) cases of incident CVD. A large SUA variation (top vs. bottom tertiles) was associated with a higher risk of CVD (hazard ratio [HR], 1.24; 95% confidence interval [CI], 1.11–1.40), especially in older adults than that in young adults (P int =0.0137). The higher risk of CVD was observed with both large rises (HR, 1.24; 95% CI, 1.10–1.39) and falls (HR, 1.19; 95% CI, 1.03–1.38) in SUA variation. The hazardous effect of SUA variation on CVD was mainly induced by excessive inflammation and elevated blood pressure. Similar results were observed for CVD subtypes. Elevated SUA variation was associated with a higher risk of CVD, irrespective of the direction of SUA variation, and inflammation played an important role in the pathway. [ABSTRACT FROM AUTHOR]