Objective— It has been suggested that the overall effect of the major proinflammatory cytokine interleukin-1 (IL-1) on coagulation and fibrinolysis is prothrombotic. The aim of this study was to investigate whether common variations in IL1B , IL1RN , IL1R1 , and IL1R2 influence the risk of venous thrombosis. Methods and Results— In a case–control study on the causes of deep venous thrombosis, the Leiden Thrombophilia Study (LETS), we genotyped 18 single nucleotide polymorphisms (SNPs) in IL1B , IL1RN , IL1R1 , and IL1R2 , enabling us to tag a total of 25 haplotype groups. Overall testing of the haplotype frequency distribution in patients and controls indicated that a recessive effect was present in IL1RN ( P =0.031). Subsequently the risk of venous thrombosis was calculated for each haplotype of IL1RN . Increased thrombotic risk was found for homozygous carriers of haplotype 5 (H5, tagged by SNP 13888T/G, rs2232354) of IL1RN (Odds ratio=3.9; 95% confidence interval: 1.6 to 9.7; P =0.002). No risk was associated with haplotype 3 of IL1RN , which contains the frequently examined allele 2 variant of the intron 2 VNTR. Conclusions— We found that IL1RN –H5H5 carriership increases the risk of venous thrombosis.