Background and Objective: Few prospective studies exist evaluating the safety and efficacy of the Pipeline Embolization Device (PED) in the treatment of intracranial aneurysms. The Aneurysm Study of Pipeline In an observational Registry (ASPIRe) study prospectively analyzed rates of complete aneurysm occlusion and neurologic adverse events following PED treatment of intracranial aneurysms. Materials and Methods: We performed a multicenter study prospectively evaluating patients with unruptured intracranial aneurysms treated with PED. Primary outcomes included (1) spontaneous rupture of the Pipeline-treated aneurysm; (2) spontaneous nonaneurysmal intracranial hemorrhage (ICH); (3) acute ischemic stroke; (4) parent artery stenosis, and (5) permanent cranial neuropathy. Secondary endpoints were (1) treatment success and (2) morbidity and mortality at the 6-month follow-up. Vascular imaging was evaluated at an independent core laboratory. Results: One hundred and ninety-one patients with 207 treated aneurysms were included in this registry. The mean aneurysm size was 14.5 ± 6.9 mm, and the median imaging follow-up was 7.8 months. Twenty-four aneurysms (11.6%) were small, 162 (78.3%) were large and 21 (10.1%) were giant. The median clinical follow-up time was 6.2 months. The neurological morbidity rate was 6.8% (13/191), and the neurological mortality rate was 1.6% (3/191). The combined neurological morbidity/mortality rate was 6.8% (13/191). The most common adverse events were ischemic stroke (4.7%, 9/191) and spontaneous ICH (3.7%, 7/191). The complete occlusion rate at the last follow-up was 74.8% (77/103). Conclusions: Our prospective postmarket study confirms that PED treatment of aneurysms in a heterogeneous patient population is safe with low rates of neurological morbidity and mortality. Patients with angiographic follow-up had complete occlusion rates of 75% at 8 months.