Dexamethasone is an effective prophylaxis against postoperative nausea and vomiting but is immunosuppressive and may predispose patients to an increased postoperative infection risk. This matched case-control study examined the association between the administration of a single intraoperative anti-emetic dose of dexamethasone (4 to 8 mg) and postoperative infection in patients undergoing non-emergency surgery in a university trauma centre. Cases were defined as patients who developed infection between one day and one month following an operative procedure under general anaesthesia. Controls who did not develop infection were matched for procedure, age and gender Exclusion criteria included immunosuppressive medications, chronic glucocorticoid therapy, cardiac surgical and solid-organ transplantation procedures. Sixty-three cases and 172 controls were identified. Cases were more likely to have received dexamethasone intraoperatively (25.4 vs. 11%, P = 0.006), and less likely to have received perioperative antibiotic prophylaxis (60.3 vs. 84.3%, P = 0.001). Stepwise, multivariate conditional logistic regression confirmed these associations, with adjusted odds ratios of 3.03 (1.06 to 19.3, P = 0.035) and 0.12 (0.02 to 0.7, P = 0.004) respectively for the associations between dexamethasone and perioperative antibiotic prophylaxis, with postoperative infection. We conclude that intraoperative administration of dexamethasone for anti-emetic purposes may confer an increased risk of postoperative infection.