The genes in the IL-1 complex code for three proteins, IL-1alpha, IL-1beta and the IL-1 receptor antagonist (IL-1 Ra). The severity of a given infection is influenced by the balance between the levels of IL-1beta, the major extracellular agonist, and that of IL-1 Ra. In healthy individuals, IL-1 Ra is readily detectable in plasma but IL-1beta levels are usually undetectable. As there are polymorphisms in both of these genes, we have now analyzed whether there are allelic associations between these loci and whether these would have an influence on plasma IL-1 Ra levels. In 200 healthy blood donors, the mean plasma IL-1 Ra concentration was 681 pg/ ml. The IL-1Ra allele 2 (IL1RN*2) had a clear influence on IL-1Ra levels: its carriers had higher levels than the non-carriers (745 ng/ml vs. 627 pg/ml, p < 0.05, t-test). As marker alleles for IL-1beta we used two biallelic base-exchange polymorphisms (at positions -511 and +3953 relative to the transcriptional start site). The more rare allele of IL-1beta -511 (allele 2) was significantly associated with the presence of IL-1 Ra allele 2, but in the case of the IL-1beta +3953, the more rare allele (allele 2) was less frequent in the carriers of the IL-1 Ra allele 2. These IL-1beta allelisms did not have a direct influence on plasma IL-1Ra levels, but the enhancing effect of IL-1 Ra allele 2 on IL-1 Ra plasma levels required the presence of the IL-1beta -511 allele 2 or absence of the IL-1beta +3953 allele 2. Taken together, these results indicate that the IL-1beta gene participates in the regulation of IL-1 Ra production in vivo and that the alleles of IL-1beta and IL-1 Ra which demonstrate this cooperative effect are often associated.