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Introduction: Abdominal surgery results in a massive inflammation within the intestinal wall leading to postoperative ileus. Previous results suggested that resident macrophages within the intestinal muscularis play an important role in the local inflammatory process. Aim of this study was to determine if depletion and inactivation of these macrophages would lead to a reduction of the inflammation and subsequently to normalization of smooth muscle function. Methods: Rats underwent intestinal manipulation. Depletion and inactivation-groups were pretreated i.v. with clodronate-encapsulated-liposomes and gadolinium chloride. Cytokine mRNA expression (IL-1b, IL-6, TNF-a) was determined by real-time RT-PCR in isolated bowel wall layers. Muscularis whole mounts were used for histo- and immunohistochemistry to quantify leukocytes. In-vivo gastrointestinal transit and in-vitro muscle contractility in a standard organ bath were measured. Statistical analysis was done with the student t-test and ANOVA, p Results: Pretreatment resulted in 85% depletion of muscularis macrophages. Intestinal manipulation led to a massive leukocyte recruitment (neutrophils (PMN): 155.5-fold), a significant up-regulation of cytokines (3h postoperatively: IL-1β: 20.3fold, IL-6: 33.2-fold) and a significant decline in muscle contractility in-vivo and in-vitro. Pretreament significantly reduced the inflammatory reaction (PMN: 75.6%; IL-1β: 63.5%, IL-6: 50.6%) and averted muscle dysfunction. Conclusions: These data show that depletion and inactivation of resident muscularis macrophages decrease the local inflammatory response and smooth muscle dysfunction following surgical intestinal trauma. Therefore, this study shows for the first time that resident macrophages of the intestinal muscularis are causally involved in the local inflammatory reaction and subsequent functional impairment of the smooth muscle, which leads to postoperative ileus.