Abstract Background In humans, uric acid is the final metabolite of adenosine triphosphate, an energy source. Xanthine oxidase (XO) contributes to urate metabolism, and XO inhibitors (XOI) suppress the production of uric acid and could store ATP. However, recent studies showed that discontinuation of XOI may lead to ATP depletion and increased death as a withdrawal syndrome. We examined whether the XOI withdrawal syndrome actually occurs. Methods This study retrospectively analyzed the Japanese Registry Of All cardiac and vascular Diseases (JROAD) database, which included 8,927,858 patients out of 9,825,635 data from April 2014 to March 2020, excluding 330,847 patients younger than 20 years and 566,930 patients older than 90 years. Of these, 356,405 were hospitalized patients with cardiovascular disease who were receiving uric acid-lowering drugs, and 315,388 were on XOI (41,017 were on other uric acid-lowering medications)(Fig). The XOI adherents were divided into the following four groups, and the number of deaths and mortality rates for each were identified as follows. Results (1) Those who were on the drug at admission and continued the drug at discharge: 219,020 cases, of which 59 deaths (0.03%). (2) 89,035 patients were discharged from the hospital on the medication they were on at the time of admission, of which 17,663 died (19.84%). (3) 7,241 patients who were not on any medication at admission (medication was given during hospitalization) and continued on medication at discharge, including 11 deaths (0.15%). (4) No medication at admission (medication was given during hospitalization) and stopped at discharge: 92 cases, of which 11 deaths (11.96%). Continuous medication group: 226,261 cases, including (1) and (3), of which 70 deaths, (0.03%). Withdrawal group: 89,127 cases, including (2) and (4), of which 17,674 deaths (19.8%). The number of deaths in the withdrawal group was 620 times higher than that in the continuation group (p<0.001). Conclusion XOI withdrawal syndrome is detected in our study. However, some of the deaths in the XOI discontinuation group were due to the fact that other medications were also discontinued, which indicate impossible to determine a direct causal relationship between XOI withdrawal and death. Further studies are needed to check the relationship between XOI withdrawal and death in other algorithms.Fig. Flow-chart of the study