ObjectiveHospital‐acquired infections are a common complication for patients with moderate or severe traumatic brain injury (TBI), contributing to morbidity and mortality. As infection‐mediated immune responses can predispose towards epilepsy, we hypothesized that post‐injury hospital‐acquired infections increase the risk of post‐traumatic epilepsy (PTE).MethodsA retrospective cohort study of adults with moderate to severe TBI was conducted using data from the Victorian State Trauma Registry in Australia. Infections were identified from the International Statistical Classification of Diseases and Related Health Problems 10th Revision–Australian Modification (ICD‐10‐AM) codes, and diagnosis of PTE was determined by the Glasgow Outcome Scale – Extended questionnaire regarding epileptic fits at 24 months follow‐up.ResultsOf all TBI patients (n = 15 152), 24% had evidence of having had any type of infection, with the most common being pneumonia, urinary tract, and respiratory infections. Of those who responded to the PTE question at 24 months (n = 1361), 11% had developed PTE. Univariable analysis found that the incidence of PTE was higher in patients who had any type of infection compared to patients without an infection (p < 0.001). After adjustment for covariates associated with both development of PTE and risk of infection, multivariable analysis found a solid association between infection and PTE (adjusted RR = 1.59; 95% CI: 1.11–2.28; p = 0.011). Having any type of complicating infection acquired during admission was also associated with poor GOSE outcomes at subsequent follow‐ups (adjusted OR = 0.20; 95% CI: 0.11–0.35, p < 0.001).SignificanceThese findings suggest that hospital‐acquired infections contribute to PTE development after TBI. Future investigation into infections as a modifiable target to reduce poor outcomes after TBI is warranted.Plain Language SummaryHospital‐acquired infections are common in patients with traumatic brain injuries. A database study of adults with moderate or severe brain injuries in Australia examined whether these infections are associated with the development of epilepsy after a brain injury. 24% of patients had infections, with pneumonia and urinary tract infections being the most common. Of those surveyed 2 years after the injury, 11% developed post‐traumatic epilepsy. Patients with infections had a significantly higher risk of epilepsy, even when accounting for other known risk factors, and infections were also linked to poor outcomes more broadly. The study suggests that preventing hospital‐acquired infections could be a crucial target for improving outcomes after traumatic brain injuries.