<p>This retrospective study explores the prognostic significance of the frequency and persistence of Neurological Pupil index (NPi) differentials (NPi-d) in patients with acute brain injury admitted to the intensive care unit. A total of 57 patients with traumatic brain injury, subarachnoid hemorrhage, or intracerebral hemorrhage were included, all of whom underwent serial quantitative pupillometry. An NPi-d was defined as a difference of ≥ 0.7 between the NPi of the two pupils, while the persistence of the differential (pNPi-d) captured sustained asymmetry over time, regardless of whether the threshold was reached. The analysis revealed that both the number of NPi-d events and the pNPi-d were significantly associated with unfavorable neurological outcomes and mortality at intensive care unit (ICU) discharge. Multinomial logistic regression showed that an increased number of NPi-d was associated with a more than threefold increased risk of poor outcome and death. Similarly, higher pNPi-d values correlated with greater odds of poor outcome, death, elevated need for therapeutic interventions to manage intracranial hypertension, decompressive craniectomy, and longer ICU stay. These findings suggest that, beyond static NPi thresholds, dynamic measures such as the frequency and persistence of NPi asymmetries provide valuable prognostic information. Incorporating these pupillometry-based metrics into routine neuromonitoring could enhance early risk stratification and guide treatment strategies in critically ill neurological patients.</p>