Hypophosphatemia, a common metabolic disorder, is usually silent and diagnosed by blood tests. However, misdiagnosis may result in delayed phosphate repletion, responsible for significant morbidity and potential mortality. We report an exceptional case of hypophosphatemia-related, life-threatening encephalopathy. A 49-year-old type-1 diabetic woman was admitted to our intensive care unit with coma and severe ketoacidosis. Initial neurologic impairment worsened despite improvement in acid-base disturbances and glucose levels. The electroencephalogram showed bilateral spikes with a background theta wave rhythm. Profound hypophosphatemia <0.20 mmol/L (<0.6 mg/dL) was diagnosed. No other cause of encephalopathy was found. Prompt phosphate repletion resulted in progressive and complete recovery. This observation allowed us to study the relations between the coma depth, the electroencephalographic findings, and the serum phosphate concentrations. Our data strongly suggest that phosphate depletion-induced encephalopathy probably originates from direct impairment of cerebral electrophysiological activity rather than from cardiac flow alteration.