It is now well established that the pathophysiology of the malignant hyperthermia (MH) syndrome is related to a malfunction of intracellular calcium homeostasis. Magnesium plays important roles in the basic contractile properties of muscle, and many of its actions are antagonistic to those of calcium. The aim of this study was to determine the effectiveness of magnesium sulphate to prevent the MH episode in susceptible animals and correlate this with its effects on the intracellular free calcium ([Ca2+]i). The experiments were carried out using six control (Yorkshire) and ten MH-susceptible crossbred swine (Poland China X Pietrain). After determination of resting concentrations of [Ca2+]iand [Mg2+]i, each animal was given either two iv bolus doses of 50 mg/kg or one iv bolus of 100 mg/kg of MgSO4. The resting [Ca2+]iand [Mg2+]iwere determined by means of ion-selective microelectrodes. The resting [Ca2+]iin normal muscle fibers was 0.11 ± 0.01 μM (mean ± SEM), whereas in the MH muscles the resting [Ca2+]iwas 0.36 ± 0.01 μM. In neither group was the resting [Ca2+]imodified by MgSO4. This cumulative dose of MgSO4(100 mg/kg) was not able to prevent the induction of an MH episode by 2% halothane. Although MgSO4did not directly decrease [Ca2+]i, it did attenuate the increase in [Ca2+]iassociated with the syndrome from 7.29 ± 0.43 μM in untreated animals to 0.84 ± 0.03 μM in MgSO4pretreated swine. In addition, the limb rigidity that accompanies this increase in calcium was prevented by MgSO4pretreatment. Baseline measurements of [Mg2+]iwere not different in control and MH-susceptible muscles. Administration of MgSO4(100 mg/kg) increased [Mg2+]i1.8-fold (P< 0.001). These results indicate that MgSO4by itself was ineffective both in decreasing resting [Ca2+]iand in preventing the changes associated with the MH episode. However, MgSO4was able to quantitatively reduce the increase in [Ca2+]i, prevent the limb rigidity, and reduce the increment in body temperature usually associated with the clinical syndrome.