Interleukin-1 (IL-1) is a potent stimulator of bone resorption and is strongly implicated in the destruction due to bystander damage seen in periodontal disease. Recent studies suggest that polymorphisms of the (IL-1) gene complex may be significant risk factors for a number of chronic inflammatory diseases. The severity of periodontal disease has been positively associated with carriage of allele 2 at position -889 of the IL-1A gene in conjunction with allele 2 of the IL-1B gene at position +3953. In this study, we tested the hypothesis that allele 2 of the IL-1A gene at position -889 might act to elevate levels of IL-1alpha protein in patients with periodontal disease. Since levels of IL-1alpha protein are low in healthy individuals, we used a group of patients with severe periodontal disease to investigate if levels of IL-1alpha protein in gingival crevicular fluid can be correlated to patient genotype. IL-1alpha levels were measured by enzyme immunoassay in 46 patients with severe periodontal disease. These patients were genotyped by PCR and allele-specific restriction digests. The carriage rate for allele 2 in the diseased population was 68%. Overall, the carriage of allele 2 was associated with almost a four-fold increase in IL-1alpha protein levels. Differences were most pronounced in non-smokers, while heavy smokers showed reduced levels of IL-1alpha protein regardless of genotype. These results suggest a mechanism whereby this genetic polymorphism acts to modulate IL-1alpha protein production and may influence the pathogenesis of periodontal disease by affecting the extent of IL-1-associated bystander damage.