Objective To establish the safety and efficacy of endovascular repair of thoracoabdominal aortic aneurysms. Methods Between May 2004 and February 2006, patients with thoracoabdominal aneurysms considered high risk for conventional surgery were enrolled in a prospective trial to evaluate a novel endovascular grafting system. Devices were custom designed for each patient using high-resolution computed tomography. Patient data included mortality, morbidity, procedural details, and surrogate end points for endovascular repair. These were collected at hospital discharge and at 1, 6, and 12 months. Results Seventy-three patients underwent endovascular repair of thoracoabdominal aortic aneurysms for type I, II, or III (n = 28), or for type IV (n = 45) thoracoabdominal aneurysms. Mean aneurysm size was 7.1 cm (range 4.5–11.3 cm). General anesthesia was used in 47% of patients and regional anesthesia in 53%. There were no conversions to open surgery nor ruptures post-treatment. Technical success was achieved in 93% of patients (68/73). Thirty-day mortality was 5.5% (4/73). Major perioperative complications occurred in 11 (14%) patients and included paraplegia (2.7%, 2/73), new onset of dialysis (1.4%, 1/73), prolonged ventilator support (6.8%, 5/73), myocardial infarction (5.5%, 4/73), and minor hemorrhagic stroke (1.4%; 1/72). A majority of patients had no complications. Mean length of stay was 8.6 days. At follow-up, 6 deaths had occurred. There were no instances of stent migration nor aneurysmal growth. Conclusions Endovascular repair of aortic aneurysms involving the visceral segment in nonsurgical candidates is feasible. Known complications of repair are not eliminated, but morbidity and mortality appeared low relative to the high-risk population studied. Further refinement of device design, delivery technique, and patient selection is ongoing. Assessment of durability will require longer follow-up.