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Very few studies have evaluated the association of articular hypermobility and radiographic osteoarthritis (OA) in humans. We assessed hypermobility and its relationship to radiographic hand OA in a family-based study.A total of 1,043 individuals were enrolled in the multicenter Genetics of Generalized Osteoarthritis study, in which families were required to have 2 siblings with radiographic OA involving ≥3 joints (distributed bilaterally) of the distal interphalangeal (DIP), proximal interphalangeal (PIP), or carpometacarpal (CMC) joint groups, and OA in at least one DIP joint. Radiographic OA was defined as a score of ≥2 on the Kellgren/Lawrence scale in one or more joints within the group. The Beighton criteria for assessment of hypermobility were recorded on a 0–9-point scale. Hypermobility was defined as a Beighton score of ≥4, a threshold generally used to establish a clinical diagnosis of joint laxity. A threshold of ≥2 was also evaluated to assess lesser degrees of hypermobility. The Beighton score for the present was calculated based on clinical examination, and that for the past was based on recall of childhood hypermobility in the first 2 decades of life. The association of hypermobility and radiographic OA of the PIP, CMC, and metacarpophalangeal joints was evaluated in all participants and in men and women separately. Multiple logistic regression was used to examine the relationship of hypermobility with radiographic OA in each joint group, after adjusting for age and sex. The association of hypermobility and DIP OA was not evaluated, because evidence of DIP OA was required for study inclusion.Using a threshold Beighton score of 4, 3.7% of individuals were classified as hypermobile based on the present examination, and 7.4% were classified as hypermobile based on the past assessment. A significant negative association between present hypermobility and age was observed. In persons with hypermobility, the odds of OA in PIP joints was lower (for present, odds ratio [OR] 0.34, 95% confidence interval [95% CI] 0.16–0.71; for past, OR 0.43, 95% CI 0.24–0.78). Similar results were obtained using a threshold Beighton score of 2. The lower odds of PIP OA with hypermobility were significant after adjusting for sex and age (for present, OR 0.44, 95% CI 0.20–0.94; for past, OR 0.48, 95% CI 0.26–0.87).This study demonstrated a joint-protective effect of hypermobility for radiographic OA of PIP joints. In contrast to previous studies showing an association of hypermobility and CMC OA, in this cohort there was no evidence for increased odds of OA in any joint group of the hand in association with articular hypermobility.