The number of people taking statins is increasing as cardiovascular risk thresholds for statin prescription are reduced across the globe. Understanding statin-induced myopathy, the most common side-effect, is paramount. We have previously shown that statin treatment in vivo increases sarcoplasmic reticulum (SR) Ca2+ leak from skeletal muscle linked with mitochondrial Ca2+ uptake and ROS production. Here we test the hypothesis that ROS-dependent post-translational modifications of the ryanodine receptor 1 (RyR1) and changes in the RyR1 molecular complex contribute to statin-induced leak. White gastrocnemius (GAS) was dissected from male Wistar rats given simvastatin (40 mg/kg/day) or saline by oral gavage for 4 weeks. Human vastus medialis samples were obtained from patients at St James’ University Hospital. All animal experimentation was carried out in accordance with the Directive 2010/63/EU of the European Parliament. Human data was approved by the Local Research Ethics committee and complies with the principles outlined in the Declaration of Helsinki. Individuals taking statins were age- and sex-matched with control subjects. Data from n=10-11 rats and n=13-13 patients were compared with the Student’s t-test. In RyR1 immunoprecipitated from GAS homogenates, statin treatment had no effect on RyR1 nitration (P>0.05) but increased phosphorylation at Ser2840 (P<0.01), linked with a loss of FKBP12 (P<0.01), but not calmodulin (P>0.05), from the complex. Data from human vastus medialis RyR1 confirm results obtained with rodent GAS i.e. marked loss of FKBP (P<0.01) in the statin-treated group. FKBP normally acts to hold the RyR1 in a closed state; its loss will promote SR Ca2+ leak. One of the effectors of phosphorylation at the Ser2840 site of RyR1 is CaM kinase II (CaMKII), whose activity is regulated by ROS via oxidation of the regulatory domain. Statin treatment promoted an increase in oxidised CaMKII (P<0.05) without any change in CaMKII expression (P>0.05). Our data suggest that statin treatment increases ROS which activates CaMKII, phosphorylating the RyR and increasing its open probability. We propose that SR Ca2+ leak creates a vicious cycle whereby Ca2+ taken up by the closely apposed mitochondria triggers further production of ROS which acts to maintain the leak. Apoptosis is another consequence of mitochondrial Ca2+ overload and ROS production, and in both rodent GAS and human vastus medialis, statin treatment produced an increase (P<0.05) in the cleavage of caspase-3, the end-effector of apoptosis. SR Ca2+ leak is a mechanism common to several types of skeletal myopathy. Here, for the first time, we describe a mechanism for the SR leak induced by statin. Defining the cellular process that underlies statin-induced myopathy is the first step in the development of co-therapies to improve statin compliance.