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Background: Early neurological deterioration (END) is a feared complication of acute cerebral ischemia, but studies have provided widely varying estimates of END frequency, have often not systematically investigated END mechanism, and have not characterized END frequency among hyperacute patients presenting within the first 2h of onset, during the period of greatest neurologic deficit lability.Methods: We analyzed subjects with a final diagnosis of acute cerebral ischemia in the NIH Field Administration of Stroke Therapy-Magnesium Phase 3 multicenter clinical trial. END was defined as worsening by ≥ 4 NIHSS points up to Day 4. Causes of worsening were adjudicated by a central expert panel reviewing detailed medical records and imaging studies.Results: Among 1245 acute cerebral ischemia patients transported by EMS to 55 receiving stroke centers, time from last known well to ED arrival was median 59 mins (IQR 80-46). Overall, 211 (16.9%) experienced END by Day 4, including 17.4% within the first 6 hours of ED arrival, 32.2% between 6-24h, and 50.3% between 24h-Day 4. Patient features associated with END included older age (73.1 vs 70.5, p=0.01), worse initial deficits (NIHSS 13.1 vs 8.4, p<0.0001), history of hypertension, diabetes, higher serum glucose, BUN, and creatinine. Arrival imaging findings associated with END included more advanced acute ischemic change (ASPECTS 7.8 vs 8.8, p<0.0001) and presence of prior infarction. Leading causes of END were: extension of initial cerebral infarct (contributing in 50.6% of END patients), cerebral edema (25.3%), hemorrhagic transformation (23.0%), and infection (8.4%). END was associated with substantially reduced functional independence (mRS 0-2) at 90 days, 9.1% vs 67.9%, p<0.0001, and increased 90-day mortality, 42.1% vs 6.5%, p<0.0001).Conclusions: END occurs in 1 in 6 hyperacute cerebral ischemia patients, and is associated with dramatic reductions in functional independence and increases in mortality by 3 months. The leading causes of END are ischemia progression, cerebral edema, and hemorrhagic transformation, which collectively contribute to 4 in 5 of all END events, and are important treatment targets to improve ischemic stroke outcome.