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Complex abdominal wall defects (CAWDs) can be difficult to repair and using a conventional synthetic mesh is often unsuitable. A biological mesh might offer a solution for CAWD repair, but the clinical outcomes are unclear. Here, we evaluated the efficacy of a cross-linked, acellular porcine dermal collagen matrix implant (Permacol) for CAWD repair in a cohort of 60 patients. Here, 58.3% patients presented with a grade 3 hernia (according to the Ventral Hernia Working Group grading system) and a contaminated surgical field. Permacol was implanted as a bridge in 46.7%, as an underlay (intraperitoneal position) in 38.3% and as a sublay (retromuscolar position) in 15% of patients. Fascia closure was achieved in 53.3% of patients. The surgical site occurrence rate was 35% and the defect size significantly influenced the probability of post-operative complications. The long-term (2 year) hernia recurrence rate was 36.2%. This study represents the first large multi-centre Italian case series on Permacol implants in patients with a CAWD. Our data suggest that Permacol is a feasible strategy to repair a CAWD, with acceptable early complications and long-term (2 year) recurrence rates.