Malignant Hyperthermia (MH) is a potentially fatal pharmacogenetic syndrome caused by exposure to halogenated volatile anesthetics and/or depolarizing muscle relaxants. We have measured intracellular calcium concentration ([Ca²⁺]_i), using doublebarreled Ca²⁺-selective microelectrodes in myoballs prepared from skeletal muscle from malignant hyperthermia susceptible (MHS) and non- susceptible (MHN) swine. Resting [Ca²⁺]_i was aproximately 2 fold higher in MHS quiescent myoballs than in MHN quiescent myoballs (232±35 vs. 112±11 nM). Treatment of myoballs with caffeine or 4-chloro-m-cresol (4-CmC) produced an elevation of [Ca²⁺]_i in both groups, however the concentration required to cause a rise in intracellular Ca2+ elevation was 4-fold lower in MHS than in MHN. Incubation of MHS cells with the fast complexing Ca²⁺ buffer BAPTA, reduced [Ca²⁺]_i, raised the concentration of caffeine and 4-CmC required to cause an elevation of intracellular Ca²⁺ and reduced the amount of Ca²⁺ release associated with exposure to any given concentration of caffeine or 4-CmC to MHN levels. These results suggest that the differences in the response of MHS skeletal myoballs to caffeine and 4-CmC appears to be mediated, at least in part, by the chronic high resting calcium found in these cells.