The repair of difficult abdominal wall defects (AWDs) continues to be a crucial and demanding issue for surgeons. This study aimed to present the risk factors and the long-term results of usage of an expanded-polytetrafluoroethylene (e-PTFE) synthetic mesh for the AWR of difficult abdominal wall defects. This study included 156 adult patients who underwent difficult AWR with e-PTFE mesh for incisional hernia, ventral hernia, and created AWDs of various etiopathologies. The association between the risk factors and the postoperative complications of AWR was analyzed, and overall long-term outcomes of e-PTFE repair were assessed. The median follow-up duration was 119.1 (ranging from 2 to 206) months. In 70 (44.8%) patients, there were major co-morbidities. A surgical site infection developed in 17 (10.9%) patients. Of these, only 2 (1.3%) patients had e-PTFE mesh infection. Seven (4.4%) patients experienced recurrence. Recalcitrant seroma formation occurred in 8 (36.3%) patients. E-PTFE synthetic mesh usage for difficult abdominal wall hernias can help the hernia surgeon obtain safe and durable long-term results of sound repair.