Objective Multiple trauma is associated with a remarkable risk of in-hospital complications, which harm healthcare services and patients. This study aimed to assess the incidence of posttrauma complications, their relationship with poor outcomes, and the effect of the Injury Severity Score (ISS) on their occurrence.Methods This retrospective cohort study was conducted at a pair of trauma centers, between January 2020 and December 2022. All hospitalized adult patients with multiple trauma were included in this study. Multivariable logistic regression was used to identify factors related to posttrauma complications.Results Among 727 multiple trauma patients, 90 (12.4%) developed in-hospital complications. The most frequent complications were pneumonia (4.8%), atelectasis (3.7%), and superficial surgical site infection (2.5%). According to multivariable logistic regression, ISS, the length of stay in the intensive care unit (ICU), the length of stay in the hospital, and mortality were significantly associated with complications. The complication rate increased by 17% with every single-unit increase in ISS (adjusted odds ratio [OR], 1.17; 95% confidence interval [CI], 1.00–1.38). Per every 1-day increase in the ICU or hospital stay, the complication rate increased by 65% (adjusted OR, 1.65; 95% CI, 1.00–2.73) and 20% (adjusted OR, 1.20; 95% CI, 1.03–1.41), respectively. Posttrauma complications were also significantly more common in patients with mortality (adjusted OR, 163.30; 95% CI, 3.04–8,779.32). In multiple trauma patients with a higher ISS, the frequency, severity, and number of complications were significantly increased.Conclusion In-hospital complications in multiple trauma patients are frequent and associated with poor outcomes and mortality. ISS is an important factor associated with posttrauma complications.