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Purpose: Complex enteric fistulas (CEF) represent general surgeons’ nightmare. This paper aims to explore the impact on failure-to-rescue (FTR) rate of a standardised and integrated surgical and critical care step-up approach. Methods: This was a retrospective observational cohort study. Patients treated for CEF from 2009 to 2019 at Niguarda Hospital were included. Each patient was approached following a three-step approach: study phase, sepsis control and strategy definition phase, and surgical rescue phase. Results: Sixteen patients were treated for CEF. Seven fistulas were classified as complex entero-cutaneous (ECF) and nine as entero-atmospheric fistula (EAF). Median number of surgical procedures for fistula control before definitive surgical attempt was 11 (IQR 2–33.5). The median time from culprit surgery and the first access at Niguarda Hospital to definitive surgical attempt were 279 days (IQR 231–409) and 120 days (IQR 34–231), respectively. Median ICU LOS was 71 days (IQR 28–101), and effective hospital LOS was 117 days, (IQR 69.5–188.8). Three patients (18.75%) experienced spontaneous fistula closure after conversion to simple ECF, whereas 13 (81.25%) underwent definitive surgery for fistula takedown. Surgical rescue was possible in nine patients. Nine patients underwent multiple postoperative revision for surgical complications. Four patients failed to be rescued. Conclusion: An integrated step-up rescue strategy is crucial to standardise the approach to CEF and go beyond the basic surgical rescue procedure. The definition of FTR is dependent from the examined population. CEF patients are a unique cluster of emergency general surgery patients who may need a tailored definition of FTR considering the burden of postoperative events influencing their outcome.