Introduction: To investigate the pathophysiology of postoperative peritonitis and sepsis before conducting a costly clinical trial, experiments in knock-out (KO) animal models were performed (frequently in mice). The currently available sepsis models in KO mice are reductionistic or controversial and for that reason not suitable to investigate the complex neuroimmune — endocrine interactions in the perioperative period of clinical peritonitis and sepsis. The aim of this study was to establish a complex, polymicrobial sepsis model in KO mice using the concept of clinic modelling randomised trials (CMRTs) in animals to investigate the influence of the different complement activating pathways (classical, alternative, and lectin) during the perioperative course of postoperative peritonitis and sepsis. Methods: Adult male mice (20 – 25 g) were used (wild-type SV 129, C1q-/- and Bf/C2-/-). The conditions of the experiment were designed to model the clinical reality as well as the methodology of clinical trials with: sample size calculation, blinding and randomised allocation to three groups (n = 12/group), anaesthesia i.p. (fentanyl/droperidol), laparotomy and postoperative s.c. analgesia. Induction of peritonitis and sepsis were performed using a laparotomy (0.5 cm) and i.p. inocculation of a standardised polymicrobial, human faecal suspension. Dose response curves (DRC) were performed to obtain a mortality rate of 30%–50% (0.10–0.15 ml/kg BW inoculation) in the wild-type group (SV 129, six groups with n=10/group) and a following definitive study (three groups, n=12/group) for direct comparison of mortality rates and survival times. The endpoint was the 5-day mortality rate, Statistics were compiled using the chi-square test and Kaplan-Meier survival curves (log rank test). Results: The KO animal model could be established successfully. In the definitive study the obtained mortality rate for the wildtype group was 42% (5/12), 83% (10/12) in the C1q-/- group and 100% (12/12) in the Bf/C2-/- group (n=12/group, p=0.03 in global chi-square test, df=2). Sham operated animals in all three groups (i.p. Ringer solution instead of faecal suspension) did not die. Furthermore, a significant difference was obtained between the three groups in the Kaplan-Meier survival curves (n=12/group, p<0.001 in the log rank test, df=2). Discussion: A significantly increased mortality rate and a reduced survival time was obtained in the C1q-/- and in the Bf/C2-/- KO group versus the wild-type group. The relevant influence of the different complement activating pathways on the course of postoperative peritonitis and sepsis in this complex KO-mouse model is obvious. However, not only in reductionistic animal models like before, but now also in the complex scenario of CMRTs in KO mice, the important role of the complement system in peritonitis and sepsis could be demonstrated. Contributions of further investigations in this peritonitis and sepsis model can help to explain and to improve the knowledge of the complex pathophysiological course and interactions (cytokines, mediators, etc.) during sepsis.