Interleukin-1-receptor antagonist (IL-1RA) modulates the biological activity of the proinflammatory cytokine interleukin-1 (IL-1) and could play an important role in the pathophysiology of inflammatory and metabolic traits. We genotyped seven single nucleotide polymorphisms (SNPs) that capture a large proportion of common genetic variation in the IL-1RN gene in 1256 participants from the Invecchiare in Chianti study. We identified five SNPs associated with circulating IL-1RA levels with varying degrees of significance (P-value range= 0.016–4.9× 10− 5). We showed that this association is likely to be driven by one haplotype, most strongly tagged by rs4251961. This variant is only in weak linkage disequilibrium (r 2= 0.25) with a previously reported variable number of tandem repeats polymorphism (VNTR) in intron-2 although a second variant, rs579543, that tags the VNTR (r 2= 0.91), may also be independently associated with IL-1RA levels (P= 0.03). We found suggestive evidence that the C allele at rs4251961 that lowers IL-1RA levels is associated with an increased IL-1β (P= 0.03) level and may also be associated with interferon-γ (P= 0.03), α-2 macroglobulin (P= 0.008) and adiponectin (P= 0.007) serum levels. In conclusion, common variation across the IL-1RN gene is strongly associated with IL-1RA levels.