Epstein-Barr virus (EBV) seronegativity is rare in adults. To examine whether genetic differences would explain this, we studied the genetic polymorphisms of the genes of the interleukin-1 (IL-1) complex in seronegative adults. These cytokines (i.e. IL-1alpha, IL-1beta and IL-1 receptor antagonist, IL-1RA) regulate, in several ways, the inflammatory reactions of the body. In each of these genes there are polymorphic sites and the various alleles differ in their frequency in several diseases of inflammatory nature. In 400 healthy blood donors (from 18 to 60 years of age) there were 20 (5%) seronegative persons. The frequency of allele 2 of the IL-1beta gene (base exchange polymorphism at position -511 from the transcriptional start site) was decreased in the seronegative patients (0.20 versus 0.42 in the seropositive patients, P < 0.05, chi2-test). Moreover, the frequency of allele 2 of the IL-1RA (polymorphism defined by variable numbers of 86-bp repeats in intron 2) was slightly, but not significantly, decreased in the seronegative patients. Alleles of these two loci are known to be associated, but in the seronegative patients this association was abnormal: 11 out of 20 (55%) were of the IL-1RA-2 negative/IL-1beta-2 negative type, while of the seropositive patients, 25% were of this type (P < 0.01, chi2-test). These data suggest that immunological differences, depending on cytokine gene polymorphisms, regulate the resistance to EBV infection.