Mice lacking CASQ1 - a protein that modulates Ca²⁺-release channels or ryanodine receptors 1 (RYR1) - suffers of MH and EHS, life-threatening disorders triggered respectively by volatile anaesthetics and high temperature. It has been proposed that, during MH/EHS crisis, excessive oxidative stress leads to increases RYR1 Ca²⁺ leak, over-contracture and rhabdomyolysis of skeletal fibers. We treated CASQ1-null mice for 2 months with N-acetylcysteine (NAC, a potent anti-oxidant) administered in drinking water (1% w/v). NAC treatment resulted in significant protection of CASQ1-null mice from lethal episodes induced by halothane (2%, 1h at 32°C) and heat (41°C, 1h): respectively, the rate of mortality was 87 vs 25% and 77 vs 16% in controls vs NAC-treated animals. This protection is likely the results of several factors: a) reduction of oxidative stress, as shown by a decrease of mitochondrial superoxide flashes (mSOF) frequency (P<0.05); b) decreased internal temperature during heat-stress protocol (from 42.1 to 40.8 °C); and c) lower number of fibers undergoing rhabdomyolysis (from 37.6 to 11.6 %). Furthermore, NAC treatment results also in a significant increase of the threshold for caffeine-induced contracture (in-vitro contracture test). These results suggest that a) increased oxidative stress exacerbates the RYR1 instability that underlies MH/EHS episodes and b) anti-oxidants drugs should be considered for the treatment/prevention of over-heating skeletal muscle disorders.