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To determine the allele frequencies and genotype distribution of interleukin-1α, interleukin-1β, and interleukin-1 receptor antagonist gene polymorphism in septic patients.Prospective, consecutive entry study of septic patients in a general intensive care unit.A 14-bed general intensive care unit of a university hospital.Sixty patients with diagnosis of sepsis, admitted to the intensive care unit between 1997 and 1999.None.The polymorphic regions within intron 6 of interleukin-1α gene containing variable numbers of a tandem repeat (VNTR) of 46 base pairs, and intron 2 of interleukin-1 receptor antagonist gene containing VNTR of 86 base pairs, were amplified by means of polymerase chain reaction. Alleles A1–4 and RN1–4 were identified according to the size of amplified DNA product. The region containing the AvaI polymorphic site at position −511 of interleukin-1β gene was amplified by polymerase chain reaction and subsequently digested with AvaI restriction enzyme. The allele frequencies of interleukin-1 receptor antagonist RN2 and genotype RN2/2 were increased in 60 septic patients compared with normal controls (p < .01 and .05, respectively). Allele frequencies or genotype distribution of interleukin-1α VNTR gene polymorphism and interleukin-1β AvaI polymorphism did not differ between septic patients and normal controls. In addition, genotypes A2/2, B2/2, and RN2/2 were associated with a significantly higher mortality rate (70% to 80%) in septic patients. Patients with any two of the three alleles (i.e., A2, B2, and RN2) suffered from much more severe sepsis (as measured by the Acute Physiology and Chronic Health Evaluation II and Multiple Organ Dysfunction Syndrome score) and a higher mortality rate (55% to 65%), whereas septic patients with genotypes A1/1, B1/1, or RN1/1 showed a much lower mortality rate (0% to 13%).Allele interleukin-1RN2, but not interleukin-1A or interleukin-1B gene polymorphism, was associated with susceptibility to sepsis. Alleles A2, B2, and RN2 might be important high-risk genetic markers for sepsis.