Large clinical trials have helped establish the benefit of endovascular treatment (EVT) in patients with acute ischemic stroke with large vessel occlusion and small infarct core volume as determined by scores ≥6 on the Alberta Stroke Program Early CT Scores. Several small studies have suggested that patients with large infarct core volume (LICV) may also benefit from EVT. Currently, at least 6 randomized clinical trials are examining the benefit of extending EVT to this population of patients with acute ischemic stroke. These trials were independently conceived and have significant differences in their inclusion criteria. Understanding these inclusion criteria and other differences in trial design is pivotal for the field to interpret the upcoming results of these trials. In this review, the designs of the 6 trials are summarized and compared. Specific differences are described, including (1) the rationale for EVT treatment in patients with LICV, (2) how to define LICV and the imaging modality used to identify LICV, (3) inclusion of an Alberta Stroke Program Early CT Score 0 to 5 versus 3 to 5, (4) use of the mismatch between blood flow and the size of infarct as an inclusion criterion, and (5) inclusion of early window and/or late window patients. The potential impact of these trial results on current guidelines for acute ischemic stroke is discussed. Differences in trial design as well as inclusion and exclusion criteria may influence trial outcomes. The implications of these trial results will likely be enhanced by a pooled analysis.