Objective: Although uric acid lowering therapies, including xanthine oxidase (XO) inhibition, may reduce the absolute level of blood pressure (BP), the effect of XO inhibition on BP variability is largely unknown. The objective of the present analysis was to evaluate the impact of febuxostat, an XO inhibitor, on BP variability in a randomized trial setting. Design and method: This was a sub-analysis of the PRIZE study, a randomized trial to evaluate the potential effect of febuxostat on carotid intima-media thickness progression. Patients with hyperuricemia and carotid plaques were randomly assigned to the febuxostat or control group. During a 24-month period, office BP and pulse rate (PR) were measured 3 times or more. BP and PR variabilities were assessed with standard deviation (SD) and coefficient of variation (CV). The effect of febuxostat on BP and PR variabilities were adjusted with age, sex, and baseline BP or PR, expressed with 95% confidence intervals. Results: A total of 472 patients with hyperuricemia and carotid plaques were included into the present analysis. Overall, the median serum uric acid level was 7.6 [7.1, 8.2] mg/dl at baseline, and a history of hypertension was found in 419 (88.8%) patients. Baseline characteristics were well balanced between the febuxostat group (n = 236) and control group (n = 236). During the 24-month follow-up period, the febuxostat group had a significantly lower adjusted mean systolic BP (128.4 [126.8 to 130.0] vs. 130.7 [129.1 to 132.2] mm Hg, p = 0.04) and CV of systolic BP (7.4 [6.7 to 8.0] vs. 8.2 [7.6 to 8.8], p = 0.04) than the control group. Adjusted SD of PR was also lower in the febuxostat group than their counterpart (5.95 [4.93 to 6.97] vs. 7.33 [6.32 to 8.33], p = 0.04). Conclusions: XO inhibition with febuxostat was associated with reduced visit-to-visit BP variability as well as reduced PR variability, illustrating the potential therapeutic effect of febuxostat in patients with hyperuricemia and carotid plaques.