Malignant Hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle triggered in susceptible individuals by inhalation anesthetics and depolarizing skeletal muscle relaxants. This syndrome has been linked to a missense mutation in the type 1 ryanodine receptor (RyR1) in more than 50% cases studied to date. Using double-barreled Ca²⁺ microelectrodes in myotubes expressing wild type RyR1 (_WTRyR1) or RyR1 with one of four common MH mutations (_MHRyR1), we have measured resting intracellular Ca²⁺ concentration ([Ca²⁺]_i). Changes in resting [Ca²⁺]_i produced by several drugs known to modulate the RyR1 channel complex were investigated. We found that myotubes expressing any of the _MHRyR1s had a 2- to 3.7-fold higher resting [Ca²⁺]_i than those expressing _WTRyR1. Exposure of myotubes expressing _MHRyR1s to ryanodine (500µM) or [2,6-dichloro-4-aminophenyl] isopropylamine (FLA 365) (20µM) had no effects on their resting [Ca²⁺]_i. However when myotubes were exposed to bastadin 5 alone or a combination of ryanodine and bastadin 5 the resting [Ca²⁺]_i was significantly reduced (p<0.01). Interestingly the percent decrease in resting [Ca²⁺]_i in myotubes expressing _MHRyR1s was significantly greater than that for _WTRyR1. From these data we propose that the high resting myoplasmic [Ca²⁺]_i in _MHRyR1 expressing myotubes is due in part to a related structural conformation of _MHRyR1s that favors "passive" calcium leak from the sarcoplasmic reticulum (SR).