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Background: A genetic predisposition to Staphylococcus aureus bacteremia has been demonstrated in animals, suggesting that genetic differences might influence susceptibility to S aureus in humans., Objective: To determine whether a history of S aureus bacteremia in first-degree relatives increases the rate of the disease, and whether this rate is affected by the type of family relationship (that is, parent or sibling) or by how the relative acquired the infection., Design: Register-based nationwide cohort study (1992 to 2011)., Setting: Denmark., Participants: First-degree relatives (children or siblings) of patients previously hospitalized with S aureus bacteremia., Measurements: Poisson regression models were used to calculate standardized incidence ratios (SIRs) of S aureus bacteremia, with the incidence rate in the population as a reference., Results: 34 774 individuals (the exposed cohort) with a first-degree relative (index case patient) previously hospitalized with S aureus bacteremia were followed up for a median of 7.8 years (interquartile range, 3.6 to 13.0). A higher rate of S aureus bacteremia was observed among these first-degree relatives (SIR, 2.49 [95% CI, 1.95 to 3.19]) than in the background population. The estimate was significantly higher if the index case patient was a sibling (SIR, 5.01 [CI, 3.30 to 7.62]) than a parent (SIR, 1.96 [CI, 1.45 to 2.67]; interaction P < 0.0001). No interaction was observed regarding the sex of the first-degree relative (interaction P for parents = 0.85; interaction P for siblings = 0.92). Stratifying by disease acquisition revealed the highest rates in individuals exposed to index case patients with non-hospital-acquired infection. Few were infected with genetically identical bacteremia isolates., Limitation: The rarity of the outcome limited the number of variables in the multiple regression analysis, and whether nonsignificant interactions were true or caused by insufficient statistical power remains uncertain., Conclusion: A significant familial clustering of S aureus bacteremia was found, with the greatest relative rate of disease observed in individuals exposed to siblings with a history of the disease., Primary Funding Source: The Danish Heart Foundation and the Christian Larsen and Judge Ellen Larsen Foundation.