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Though implant infections are associated with inflammation, periosteal reactive bone formation, and osteolysis, the effect of obesity\/T2D on these complicating factors has not been studied. To address this question, C57BL\/6J mice were fed a high fat diet (60% Kcal from fat) to induce obesity\/T2D, or a control diet (10% Kcal from fat) for 3 months, and challenged with a transtibial pin coated with a bioluminescent USA300 strain of <jats:italic>S. aureus<\/jats:italic>. In the resulting infected bone, obesity\/T2D was associated with increased <jats:italic>S. aureus<\/jats:italic> proliferation and colony forming units. RNA sequencing of the infected tibiae on days 7 and 14 revealed an increase in 635 genes in obese\/T2D mice relative to controls. Pathways associated with ossification, angiogenesis, and immunity were enriched. MicroCT and histology on days 21 and 35 demonstrated significant increased periosteal reactive bone formation in infected obese\/T2D mice versus infected controls (<jats:italic>p\u2009<\/jats:italic>&lt;\u20090.05). The enhanced periosteal bone formation was associated with increased osteoblastic activity and robust endochondral ossification, with persistant cartilage on day 21 that was only observed in infected obesity\/T2D. Osteolysis and osteoclast numbers in obesity\/T2D were also significantly increased versus infected controls (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Consistent with an up\u2010regulated immune transcriptome, macrophages were more abundant within both the periosteum and the new reactive bone of obese\/T2D mice. In conclusion, we find that implant\u2010associated <jats:italic>S. aureus<\/jats:italic> osteomyelitis in obesity\/T2D is associated with increased inflammation, reactive bone formation, and osteolysis. \u00a9 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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