Introduction Treatment of large (≥20 mm) and giant (≥25 mm) intracranial aneurysms is challenging and can be associated with a high rate of morbidity and mortality. The Pipeline Embolization Device (PED) has been used effectively for the treatment of intracranial aneurysms achieving a high rate of complete occlusion. However, its safety and efficacy in treatment of large and giant aneurysms has not been evaluated fully. Methods A retrospective analysis of consecutive aneurysms treated with PED between 2009 and 2016 at 3 academic institutions within the United States was performed. Large (≥20 mm) and giant aneurysms (≥25 mm) were selected for evaluation of occlusion and complication rates following treatment with PED. Results A total of 50 large and giant aneurysms were individually treated using PED. Aneurysms were fusiform (74%) or saccular (26%) in morphology. PED alone was used for treating 78% of the aneurysms, whereas PED with adjunctive coiling was used for treating 22%. The median length of angiographic follow-up was 13 months (mean follow up 20.4 months). At last follow-up, complete or near-complete occlusion (90–100%) was achieved in 76.9% of aneurysms. Symptomatic thromboembolic complications were encountered in 12% of procedures and symptomatic hemorrhagic complications in 8%. Conclusions The use of PED for the treatment of large and giant intracranial aneurysms is associated with good occlusion rates, but also a greater complication rate compared to aneurysms of smaller size. There was no significant difference in occlusion rate based on aneurysm shape or size, number of PEDs placed, or adjunctive coiling.