Abstract Background The prevalence of valvular heart disease is on the rise. Severe valvular diseases are generally associated with high mortality, and aortic stenosis (AS) is associated with halved survival after out-of-hospital cardiac arrest (OHCA). Despite the severity of the prognosis of valvular heart diseases, their association with the risk of OHCA is not well-elucidated. Purpose The study aimed to examine the association between valvular heart disease and OHCA. Method We conducted a study using data from the nationwide Danish Cardiac Arrest Registry. We included adult OHCA patients with presumed cardiac origin. We compared OHCA cases with and without valvular heart disease, stratified by valvular disease type (AS, aortic regurgitation (AR), mitral stenosis (MS), and mitral regurgitation (MR) or multiple valvular diseases (more than 1 concomitant type of valvular disease)). We calculated the hazard ratios of OHCA using time-varying Cox regression models fitted with a nested case-control design. For each case, we matched up to five controls based on age, sex, year of OHCA, and two comorbidities: ischemic heart disease and congestive heart failure. Results We included 43,967 OHCA cases and 219,772 controls matched from the general population. In the total case population, the median age was 72 years, 68% were male, 26% had ischemic heart disease, 21% had congestive heart failure, and 57% had cardiovascular risk factors. We identified 1862 (4.23%) cases with AS, 336 (<1%) with AR, 31 with MS (<1%), 710 with MR (1.6%), and 605 with multiple valvular diseases (1.4%). Compared with cardiac arrest cases without valvular disease, cases with valvular disease were more likely to have ischemic heart disease (e.g., AS vs controls: 6.5% vs 1.7%, p<0.001) and congestive heart failure (e.g., MR vs controls: 3.5% vs 1%, p<0,001; AS vs controls: 8.2% vs 2.8%, p<0.001). AS, MS (HR: 1.67 [95%CI: 1.12; 2.51]), MR (HR: 1.38 [95%CI: 1.27; 1.50]) and multiple valvular diseases (HR: 1.36 [95%CI: 1.24; 1.49]) were significantly associated with higher hazard of OHCA (Figure 1); the strongest association was seen for AS (HR: 1.66 [95% CI: 1.58; 1.76]) (Figure 1). AR was not significantly associated with OHCA (HR: 1.05 [95%CI: 0.94; 1.19]). Conclusion In this Danish nationwide cardiac arrest cohort, aortic stenosis, aortic regurgitation, and mitral regurgitation were associated with increased rates of OHCA. The association was strongest in aortic stenosis patients. Focus on risk factors of OHCA in patients with valvular heart disease is warranted.Figure 1