Background: A large body of evidence is emerging to implicate that dysregulation of the gut microbiome (dysbiosis) increases the risk of surgical site infections. Gut dysbiosis is known to occur in patients with inflammatory bowel disease (IBD), allowing for translocation of bacteria across the inflamed and highly permeable intestinal mucosal wall. The null hypothesis was that IBD was not associated with an increased risk of periprosthetic joint infection (PJI) after primary total hip and knee arthroplasty.Methods: A matched cohort study was designed. The primary end point was the occurrence of PJI at 2 years postoperatively. The secondary end points were aseptic revisions at 2 years postoperatively, discharge to a rehabilitation facility, complications up to 30 days after total joint arthroplasty, and readmission up to 90 days after total joint arthroplasty. The International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) codes were used to identify patients with IBD and the control cohort. A chart review was performed to confirm the diagnosis of IBD. Using our institutional database, 152 patients with IBD were identified and matched (3:1) for age, sex, body mass index, year of surgical procedure, Charlson Comorbidity Index, and involved joint with 456 patients without IBD undergoing total joint arthroplasty. Results:The cumulative incidence of PJI was 4.61% for the patients with IBD compared with 0.88% for the control cohort (p = 0.0024). When univariable Cox regression was performed, a diagnosis of IBD was found to be an independent risk factor for PJI (hazard ratio [HR], 5.44 [95% confidence interval (CI), 1.59 to 18.60]; p = 0.007) and aseptic revisions (HR, 4.02 [95% CI, 1.50 to 10.79]; p = 0.006). The rate of postoperative complications was also higher in patients with IBD.Conclusions: Based on the findings of this study, it appears that patients with IBD are at higher risk for treatment failure due to PJI or aseptic loosening after primary total joint arthroplasty. The exact reason for this finding is not known, but could be related to bacterial translocation from the inflamed intestinal mucosa, the dysregulated inflammatory status of these patients, malnutrition, and potentially other factors. Some of the aseptic failures could be as a result of infection that may have escaped detection and/or recognition.