It is not clear whether mesh-reinforced anterior component separation (CS) for abdominal wall reconstruction (AWR) results in better outcomes than mesh-reinforced primary fascial closure (PFC) without CS, particularly when acellular dermal matrix is used. The authors compared outcomes of CS versus PFC repair in AWR procedures aiming to determine whether CS results in better outcomes. This retrospective study of prospectively collected data included 461 patients who underwent AWR with acellular dermal matrix during a 10-year period at an academic cancer center. The primary endpoint was hernia recurrence; the secondary outcome was surgical-site occurrence (SSO). A total of 322 patients (69.9%) who underwent mesh-reinforced AWR with CS (AWR-CS) and 139 (30.1%) who underwent AWR with PFC (AWR-PFC) without CS were compared. AWR-PFC repairs had a higher hernia recurrence rate than AWR-CS repairs (10.8% versus 5.3%; P = 0.002) but similar overall complication (28.8% versus 31.4%; P = 0.580) and SSO (18.7% versus 25.2%; P = 0.132) rates. CS repairs experienced significantly higher wound separation (17.7% versus 7.9%; P = 0.007), fat necrosis (8.7% versus 2.9%; P = 0.027), and seroma (5.6% versus 1.4%; P = 0.047) rates than PFC repairs. The best cutoff with respect to hernia recurrence was 7.1 cm of abdominal defect width. AWR-CS repair resulted in a lower hernia recurrence rate than AWR-PFC but, despite the additional surgery, had similar SSO rates on long-term follow-up. Therapeutic, III.