BACKGROUND: Systemic low-grade inflammation is a prognostic risk factor of atrial fibrillation (AF). OBJECTIVE: We hypothesized that genetic polymorphisms, which determine the rate of inflammatory cytokines, are associated with the risk of AF, independently of comorbidity. METHODS AND RESULTS: We included 192 patients with so-called lone AF and age 40 years or below, and 188 healthy controls. All patients were genotyped for single nucleotide polymorphisms (SNPs) in inflammatory genes using fluorescence-based real-time polymerase chain reaction (PCR). A case-control analysis of the C/C, C/T and T/T genotypes on IL1A-889 revealed a significant difference in both the frequency of genotypes (p = 0.03) and in the allelic frequency (p = 0.015). These differences were not significant after Bonferroni corrections. For IL1B-511, IL10-592, IL10-1082, IL18-137, IL18-607 and TNF-308 there were no significant differences, neither in genotype frequency, nor in allelic frequency between the lone AF patients and the controls. CONCLUSION: Our study failed to show an association between polymorphisms in inflammatory genes and early onset of lone AF. It remains to be established whether polymorphisms in inflammatory genes play a causative role in the pathophysiology of AF.