Background: To our knowledge, there is an absence of prospective randomized multicenter controlled trials evaluating both the impact of technique and mesh type on outcomes in complicated ventral hernia repair. Study Design: A prospective randomized multicenter controlled trial of 120 patients at 3 sites was conducted in which patients were randomized to either overlay (anterior component separation) or underlay mesh placement (posterior component separation) and mesh type (human acellular dermis [HADM] vs porcine acellular dermis [PADM]). Key inclusion criteria included hernia size (>200 cm 2 ), BMI < 40 kg/m 2 , hemoglobin A1C < 7%, tobacco free > 6 weeks and primary fascial closure. Primary outcome was hernia recurrence at 1 year, determined by independent examiner/imaging. Secondary outcomes included complications and patient satisfaction (short form [SF]-36v2). Standardized investigator training included a porcine model followed by a proctored first case by the lead investigator. Results: There were no significant differences in demographics between the 4 groups (age 60 ±12 years, BMI 32 ± 5 kg/m 2 , 51% female). The overall 1-year recurrence rate was 10.8%. There was no significant difference in recurrence rate by location of mesh placement (overlay 9.8%, underlay 11.9%) or mesh type (HADM 10.3%, PADM 11.3%). Overlay patients had a significantly lower surgical site infection rate (1.6% vs 11.9% p = 0.03), reported better physical functioning (p = 0.001) and role limitation scores (p = 0.04) in the early postoperative period, and achieved the highest physical functioning score during the 12-month period (p < 0.03). Conclusions: Recurrence rates were not affected by either anatomic location or type of mesh used. To our knowledge, this represents the first prospective randomized multicenter controlled trial that demonstrates similar clinical outcomes using HADM vs PADM (not inferiority, contrary to previously published literature), with several advantages identified using the overlay technique.