Abstract Background Automated infrared pupillometry (AIP) and the Neurological Pupil index (NPi) provide an objective means of assessing and trending the pupillary light reflex (PLR) across a broad spectrum of neurological diseases. NPi quantifies the PLR and ranges from 0 to 5; in healthy individuals, the NPi of both eyes is expected to be ≥ 3.0 and symmetric. AIP values demonstrate emerging value as a prognostic tool with predictive properties that could allow practitioners to anticipate neurological deterioration and recovery. The presence of an NPi differential (a difference ≥ 0.7 between the left and right eye) is a potential sign of neurological abnormality. Methods We explored NPi differential by considering the modified Rankin Score at discharge (DC mRS) among patients admitted to neuroscience intensive care units (NSICU) of 4 U.S. and 1 Japanese hospitals and for two cohorts of brain injuries: stroke (including subarachnoid hemorrhage, intracerebral hemorrhage, acute ischemic stroke, and aneurysm, 1,200 total patients) and 185 traumatic brain injury (TBI) patients for a total of more than 54,000 pupillary measurements. Results Stroke patients with at least 1 occurrence of an NPi differential during their NSICU stay have higher DC mRS scores (3.9) compared to those without an NPi differential (2.7; P  < .001). Patients with TBI and at least 1 occurrence of an NPi differential during their NSICU stay have higher discharge modified Rankin Scale scores (4.1) compared to those without an NPi differential (2.9; P  < .001). When patients experience both abnormalities, abnormal (NPi < 3.0) and an NPi differential, the latter has an anticipatory relationship with respect to the former ( P  < .001 for z-score skewness analysis). Finally, our analysis confirmed ≥ 0.7 as the optimal cutoff value for the NPi differential (AUC = 0.71, P  < .001). Conclusion The NPi differential is an important factor that clinicians should consider when managing critically ill neurological injured patients admitted to the neurocritical care units. Trial registration NCT02804438 , Date of Registration: June 17, 2016.