We present a case series of 19 patients requiring complex abdominal hernia repairs. Patients presented with challenging clinical histories with 95% having multiple significant comorbidities including overweight or obesity (84%), hypertension (53%), diabetes (42%), cancer (26%), and pulmonary disease (16%). The majority of patients (68%) had prior abdominal infections and 53% had at least one failed prior hernia repair. Upon examination, fascial defects averaged 282 cm(2). Anterior and posterior component separation was performed with placement of a human acellular dermal mesh. Midline abdominal closure under minimal tension was achieved primarily in all cases. Post-operative complications included 2 adverse events (11%) - one pulmonary embolism and one post-operative hemorrhage requiring transfusion; 6 wound-related complications (32%), 1 seroma (5%) and 1 patient with post-operative ileus (5%). Operative intervention was not required in any of the cases and most patients made an uneventful recovery. Increased patient age and longer OR time were independently predictive of early post-operative complications. At a median 2-year follow-up, three patients had a documented hernia recurrence (16%) and one patient was deceased due to unrelated causes. Conclusion: Patients at high risk for post-operative events due to comorbidities, prior abdominal infection and failed mesh repairs do well following component separation reinforced with a human bioprosthetic mesh. Anticipated post-operative complications were managed conservatively and at a median 2-year follow-up, a low rate of hernia recurrence was observed with this approach. (C) 2015 The Authors. Published by Elsevier Ltd on behalf of IJS Publishing Group Limited. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).