Abstract Background/Introduction About 10% of patients with recurrences may have a family history of pericarditis suggesting a genetic predisposition, that has been confirmed in selected cases with idiopathic recurrent pericarditis with a focused analysis of genes involved in autoinflammatory diseases (TNFRSF1A, MVK, NLRP3 genes, and variants at the Interleukin 1 Gene Locus). Purpose Aim of the present paper is to describe the frequency of detected variants of causative genes by Whole Exome Sequencing (WES) in patients with idiopathic recurrent pericarditis. Methods This is an observational, cohort study including all consecutive adult patients (>18 years) with > 2 episodes of recurrent pericarditis. All patients performed WES. We analyzed the frequency of genetic variants in: 1) known or predicted to be at least likely pathogenic (LP) variants already related to recurrent pericarditis, 2) predicted at least of unknown significance in genes not yet associated with recurrent pericarditis. Moreover, we highlighted incidental findings. Results We studied 108 patients with recurrent pericarditis (median age of 32 years, IQR 18.5; 67.6% females, all Caucasian, idiopathic etiology in 71.1%). The median number of recurrences was 5 (IQR 2). Eleven gene variants related to recurrent pericarditis were detected by WES analysis in 11/108 patients (10.2%): 9 variants were pathogenic/likely pathogenic (P/LP) according the ACMG guidelines and involved NLRP3 and TNFRSF1A genes, 2 VUS associated with familial Mediterranean fever (gene MEFV) (figure 1). We also recorded 3 P/LP variants and 2 VUS related to the inflammatory response (IFIH1, NFKBIA, JAK1, NOD2 and ALPK1 genes); 7 P/LP variants and 3 VUS related to heart’s electrical system (SCN5A, CALM2, TRPM4, KCND2, KCNQ1 genes); 12 P/LP variants and 10 VUS related to heart structural genes (figure 2). Conclusion(s) A substantial proportion of patients with multiple recurrences of pericarditis carries LP or P variants suggesting the importance of genetic predisposition evaluation in this population.