In the severely injured who survive the early posttraumatic phase, multiple-organ failure (MOF) is the main cause of morbidity and mortality. An enhanced prediction of MOF might influence individual monitoring and therapy of severely injured patients. We performed a retrospective analysis of a nationwide prospective database, the TraumaRegister DGU of the German Trauma Society. Patients with complete data sets (2002-2011) and a relevant trauma load (Injury Severity Score ISS ≥ 16), who were admitted to an intensive care unit, were included. Of a total of 31,154 patients enclosed in this study, 10,201 (32.7%) developed an MOF according to the Sequential Organ Failure Assessment score. During the study period, mortality of all patients decreased from 18.1% in 2002 to 15.3% in 2011 (p < 0.001). Meanwhile, MOF occurred significantly more often (24.6% in 2002 vs. 31.5% in 2011, p < 0.001), but mortality of MOF patients decreased (42.6% vs. 33.3%, p < 0.001). MOF patients who died survived 2 days less (11 days in 2002 vs. 8.9 days in 2011, p < 0.001). Independent risk factors for the development of MOF following severe trauma were age, ISS, head Abbreviated Injury Scale (AIS) score of 3 or higher, thoracic AIS score of 3 or higher, male sex, Glasgow Coma Scale (GCS) score of 8 or less, mass transfusion, base excess of less than -3, systolic blood pressure less than 90 mm Hg at admission, and coagulopathy. Over one decade, we observed an ongoing decrease of mortality after multiple trauma, accompanied by decreasing mortality in the subgroup with MOF. However, incidence of MOF in the severely injured increased significantly. Thus, MOF after multiple trauma remains a challenge in intensive care. The risk factors from multivariate analysis could be instrumental in anticipating the early development of MOF. Furthermore, a reliable prediction model might be supportive for patient enrolment in trauma studies, in which MOF marks the primary end point. Epidemiologic study, level III.