Acellular dermal matrices (ADMs) are used in conjunction with complex hernia repair, but their efficacy is often debated. This study assesses clinical and quality of life (QOL) outcomes in multiply comorbid patients undergoing complex ventral hernia repair using ADMs. After obtaining institutional review board approval, a prospective study was conducted evaluating patients undergoing complex ventral incisional hernia repair with abdominal wall reconstruction (AWR) using either human (Flex HD) or porcine ADM (Strattice). Patient accrual occurred over three years. Demographics, comorbid conditions, and operative details were recorded. Postoperative two-week, six-week, six-month, and one-year follow-up occurred. Primary outcomes measures include wound occurrence, QOL parameters using the Short Form-12 health survey, and hernia recurrence. Groups were compared using chi-squared, Fisher's exact, Mann-Whitney U, or t tests as appropriate. Significance was set at P < 0.05. Thirty-five patients underwent hernia repair using ADM: mean age = 58 years, mean body mass index = 34 kg/m2, >50 per cent Centers for Disease Control and Prevention Wound Class II and above, >50 per cent recurrent hernia repair, and 25 per cent current or previous mesh infection. Twenty patients (57%) experienced surgical site occurrences, 15 (43%) wound infections, and 5 (14%) recurrences with a median follow-up of one year. All Short Form-12 QOL indicators improved at 12 months compared with baseline (NS). Outcomes were similar between mesh types. In conclusion, abdominal wall reconstruction for complex hernias using biologic materials is safe but has significant morbidity. Wound complications occur in over half of all patients and are not impacted by ADM type. There is no decrement in QOL one year after hernia repair despite associated morbidity.