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Objective:. Evaluate long-term outcomes of abdominal wall reconstruction (AWR) using xenogeneic mesh in patients with Centers for Disease Control and Prevention (CDC) class III/IV defects. We hypothesized that AWR with xenogeneic mesh results in acceptable outcomes. Background:. Optimal mesh selection in AWR of CDC class III/IV defects is controversial. Outcomes using xenogeneic mesh are lacking. Methods:. We conducted a retrospective cohort study of patients who underwent AWR using xenogeneic mesh in CDC class III/IV defects from March 2005 to June 2019. Primary outcome was hernia recurrence (HR). Secondary outcomes were surgical site occurrence (SSO) and surgical site infection (SSI). Results:. Of consecutive 725 AWRs, we identified 101 patients who met study criteria. Sixty-eight patients had class III defects, while 33 had class IV defects. Patients had a mean age of 61.3 ± 11.1 years, mean body mass index of 31.8 ± 7.3 kg/m2, and mean follow-up time of 41.9 ± 26.3 months. Patients had HR rate of 21%, SSO rate of 49%, and SSI rate of 24. Class IV defects were predictive of SSOs (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.11–7.42; P = 0.029) but not HR (hazard ratio, 1.60; 95% CI, 0.59–4.34; P = 0.355) or SSIs (OR, 2.62; 95% CI, 0.85–8.10; P = 0.094). Conclusions:. Patients with class IV defects have a higher risk of SSOs, but not HR or SSIs, compared with patients with class III defects. Despite the high level of defect contamination, AWR with xenogeneic mesh demonstrated acceptable HR, SSO, and SSI rates. Therefore, safe and durable long-term outcomes are achievable in single-stage AWR using xenogeneic mesh for CDC class III/IV defects.