Although salutary effects of female sex steroids have been demonstrated not only in proestrus females but also in male animals treated with estradiol in different models of trauma, it remains unknown whether sex hormones influence post-traumatic immune response in humans. We therefore investigated the effect of sex and age on organ dysfunction and clinical course in patients with multiple injuries. Polytraumatized patients (injury severity score > 16) between 16 and 65 years old admitted to the Hannover Medical School Level 1 trauma center between January 1997 and December 2001 were included. Marshall Score for multiple organ dysfunction syndrome (MODS) was calculated for at least 14 days. The length of stay in intensive care unit and the ventilator days were recorded in addition to the number of transfusions the patient received. A total of 106 males and 37 females were included in the study. Patients with MODS had increased plasma levels of IL-6, IL-8, and IL-10. Furthermore, patients with organ dysfunction had more frequent sepsis and higher mortality rates. In addition, MODS was associated with extended length of stay in the intensive care unit and increased ventilator days. Females not older than 50 years with an injury severity score greater than 25 suffered significantly less MODS and sepsis compared with age-matched males. Moreover, they had significantly lower plasma cytokines. Thus, in this prospective study, sex difference was confirmed in MODS and sepsis, with a benefit observed in females. Although the levels of sex steroids were not measured, it seems that the protective effects may be due to estrogen effects on plasma cytokines. This suggestion is based on the fact that such salutary effects were apparent predominantly in premenopausal females.