Background: Post-traumatic sepsis is a significant cause of in-hospital death. However, socio-demographic and clinical characteristics that may predict sepsis in injured patients are not well known. The objective of this study was to identify risk factors that may be associated with post-traumatic sepsis. Methods: Retrospective analysis of patients in the National Trauma Data Bank for 2007-2008. Patients older than 16 years of age with an Injury Severity Score (ISS) ≥9 points were included. Multivariable logistic regression was used to determine association of sepsis with patient (age, gender, ethnicity, and insurance status), injury (mechanism, ISS, injury type, hypotension), and clinical (major surgical procedure, intensive care unit admission) characteristics. Results: Of a total of 1.3 million patients, 373,370 met the study criteria, and 1.4% developed sepsis, with an associated mortality rate of approximately 20%. Age, male gender, African-American race, hypotension on emergency department presentation, and motor vehicle crash as the injury mechanism were independently associated with post-traumatic sepsis. Conclusions: Socio-demographic and injury factors, such as age, race, hypotension on admission, and severity and mechanism of injury predict post-traumatic sepsis significantly. Further exploration to explain why these patient groups are at increased risk is warranted in order to understand better and potentially prevent this life-threatening complication.