Although the efficacy of endovascular treatment (EVT) in patients with anterior circulation ischemic stroke (AIS) is well documented, early neurological deterioration after EVT remains a serious issue associated with poor outcome. Besides obvious causes, such as lack of reperfusion, procedural complications, or parenchymal hemorrhage, early neurological deterioration may remain unexplained (UnEND). Our aim was to investigate predictors of UnEND after EVT in patients with AIS. Patients who underwent EVT for AIS, with an initial National Institutes of Health Stroke Scale score >5, Alberta Stroke Program Early CT Score ≥6, and included in a multicenter prospective observational registry were analyzed. Predictors of UnEND, defined as ≥4-point increase in the National Institutes of Health Stroke Scale score between baseline and day 1 after EVT, were determined via center-adjusted analyses. Among the 1925 included in the analysis, 128 UnEND (6.6%) were recorded. In multivariate analysis, predictors of UnEND were diabetes mellitus (odds ratio [OR], 2.17 [95% CI, 1.32-3.56]), prestroke modified Rankin Scale score ≥2 (OR, 2.22 [95% CI, 1.09-4.55]), general anesthesia (OR, 2.55 [95% CI, 1.51-4.30]), admission systolic blood pressure (OR, 1.10 [95% CI, 1.01-1.20]), age (OR, 1.38 [95% CI, 1.14-1.67]), number of passes (OR, 1.16 [95% CI, 1.04-1.28]), direct admission or not to a comprehensive stroke center (OR, 0.49 [95% CI, 0.30-0.81]), and initial National Institutes of Health Stroke Scale score (OR, 0.65 [95% CI, 0.52-0.81]). Severely impaired AIS patients with nonmodifiable factors are more likely to develop UnEND. Some modifiable predictors of UnEND such as the number of EVT passes could be the object of improvement in AIS management.