Objective. To assess whether genetic variation in the interleukin-1 (IL-1) gene cluster contributes to familial osteoarthritis (OA) by influencing innate ex vivo production of IL-1 or IL-1 receptor antagonist (IL-1Ra). Methods. Innate ex vivo IL-1 and IL-1Ra pro-duction upon lipopolysaccharide (LPS) stimulation of whole blood cells was measured in subjects from the Genetics, Osteoarthritis and Progression (GARP) Study, which includes sibling pairs in which at least one sibling has symptomatic OA at multiple sites. Radio-graphic OA (ROA) was assessed by Kellgren/Lawrence score. Subjects from the GARP Study and controls from the Rotterdam Study were genotyped for 7 single-nucleo-tide polymorphisms (SNPs) encompassing the IL-1 gene cluster on chromosome 2q13. Linkage disequilibrium analysis and genotype and haplotype association analy-sis were performed to assess the relationship between the IL-1 gene cluster SNPs, innate ex vivo cytokine production, and OA. Results. Among subjects in the GARP Study, the haplotype variable-number tandem repeat in intron 2/T8006C/T11100C 2/2/1 of the IL1RN gene was significantly associated with reduced innate ex vivo bioavailability of IL-1 upon LPS stimulation (P 0.026) and with ROA at the highest number of joint locations. Conclusion. These results show that genetic vari-ation at the IL-1 gene cluster is associated with lower IL-1 bioavailability and with OA at a large number of joint locations. The data further indicate that, among subjects with OA affecting the highest number of joints, the innate immune system may be activated, thereby obscuring possible underlying mechanisms. Osteoarthritis (OA) is a common joint disease and an important cause of pain and disability in the general population. Genetic factors play an important role in the etiology of various subtypes of OA (1–5). There has been a large amount of interest in the role of cytokines as mediators of joint damage and inflamma-tion in the pathogenesis of OA. Chondrocytes are known to respond to interleukin-1 (IL-1) by reducing the synthesis of matrix components and increasing the syn-thesis of matrix metalloproteinases (MMPs) (6). MMPs degrade extracellular matrix components in articular cartilage. IL-1 receptor antagonist (IL-1Ra) is the nat-ural competitive inhibitor of IL-1, occupying the cell surface IL-1 receptor without triggering signal transduc-tion, and its levels might be considered critical in determining IL-1 bioavailability (6).