Background: Peri-operative dexamethasone has been shown to effectively reduce post-operative nausea and vomiting and aide in analgesia after total joint arthroplasty (TJA); however, systemic glucocorticoid therapy has many adverse effects. The purpose of this study is to determine the effects of dexamethasone on prosthetic joint infection (PJI) and blood glucose levels in patients undergoing TJA. Methods: A retrospective chart review of all patients receiving primary TJA from 2011 to 2015 (n ¼ 2317) was conducted. Patients were divided into 2 cohorts: dexamethasone (n ¼ 1426) and no dexamethasone (n ¼ 891); these groups were subdivided into diabetic and non-diabetic patients. The primary outcome was PJI; secondary measures included glucose levels and pre-operative hemoglobin A1c (A1c) values. Statistics were carried out using logistic and regression models. Results: Of the 2317 joints, 1.12% developed PJI; this was not affected by dexamethasone (P ¼ .166). Diabetics were found to have higher rate of infection (P < .001); however, diabetics who received dexamethasone were not found to have a significantly higher infection rate that non-diabetics (P ¼ .646). Blood glucose levels were found to increase post-operatively, and dexamethasone did not increase this change (P ¼ .537). Diabetes (P < .001) and increasing hemoglobin A1c (P < .001) were also associated with increased serum glucose levels; however, this was not influenced by dexamethasone (P ¼ .595). Conclusion: Although diabetic patients were found to have a higher infection rate overall, this was not affected by administration of intravenous dexamethasone, nor was the post-operative elevation in serum glucose levels. In this study population, peri-operative intravenous dexamethasone did not increase the rate of PJI and was safe to administer in patients undergoing TJA.