Plasma levels of ionized magnesium (IMg) measured by ion-selective electrode were investigated in neonatal hyperbilirubinemia by comparing the newborns with (Ն205 M) and without (Ͻ205 M) significant hyperbilirubinemia (groups of severe and moderate hyperbilirubinemia, respectively). Serum bilirubin, plasma IMg, and ionized calcium (ICa) levels were determined in 165 healthy term newborns with nonhemolytic indirect hyperbilirubinemia during the first 10 d of life. Mean serum bilirubin, plasma IMg, and ICa levels were 200.1 Ϯ 126.5 M, 0.54 Ϯ 0.12 mM, and 1.15 Ϯ 0.12 mM, respectively, in 165 newborns whose mean postnatal age was 156.1 Ϯ 46.5 h, and there was a significant positive correlation between the mean serum bilirubin and plasma IMg levels (r ϭ 0.535, p Ͻ 0.001). Serum bilirubin levels (304.4 Ϯ 83.8 M versus 94.1 Ϯ 54.7 M) and plasma IMg levels (0.6 Ϯ 0.12 mM versus 0.49 Ϯ 0.1 mM) were significantly higher and plasma ICa levels (1.13 Ϯ 0.12 mM versus 1.18 Ϯ 0.12 mM) were significantly lower in the group of severe hyperbilirubinemia (n ϭ 83) when compared with the group with moderate hyperbilirubinemia (n ϭ 82). Seventeen of the 83 cases of severe hyperbilirubinemia had IMg levels above the normal range (Ն0.69 mM), whereas none of the 82 cases of moderate hyperbilirubinemia had elevated IMg levels. Fifteen of the 17 with high IMg levels had bilirubin levels Ͼ290 M. Results of the present study suggest that increase in plasma IMg may be due to extracellular movement of Mg, a principally intracellular ion, resulting from generalized cellular injury including neurons and erythrocytes. Considering neuroprotective functions and beneficial effects of Mg ion in improving neurologic outcome, we also may speculate the possibility of a neuroprotective role or a compensatory mechanism in IMg increase against emerging toxicity risk of increasing serum bilirubin levels. Deposition of unbound bilirubin or its acid form in the neuron membrane causes permanent neuronal injury with a distinctive regional topography throughout the CNS. Considering the affinity of bilirubin molecule to phospholipids of the plasma membrane (1-4), the sequence of membrane events initiated by bilirubin molecules damages all adjacent membrane-bound enzymes and receptors. However, distant plasma membrane structures such as N-methyl-D-aspartate (NMDA) receptor/ion channel complex located within neuronal membranes on the synaptic surface of neurons are disrupted as well. Increased and prolonged activation of NMDA receptor as in perinatal asphyxia and hypoxic ischemic encephalopathy (HIE) results in brain cell injury despite its physiologic roles in brain plasticity; neuronal growth; synaptogenesis; and development of learning, memory, and vision. However, it has been shown in newborn piglets that bilirubin also increases activation of the NMDA receptor by modifying its binding characteristics, increases the receptor's affinity for NMDA receptor antagonists, and thus results in neuronal injury (5). Bilirubin-induced neurotoxicity may share common featu...