In studies on 94 male Wistar rats changes in the hydrogen sulfide content (H2S) and cystathionine γ-lyase (CSE) in the liver and skeletal muscles in hypercholesterolemia under simvastatin treatment were assessed, as well as the effect of propargylglycine (PAG) on hepato- and myotoxicity of simvastatin. It was determined, that simvastatin inhibited the CSE-mediated synthesis of H2S in the main target organs. This negatively affected their biochemical and functional status. The use of PAG significantly suppressed the H2S deficiency induced by simvastatin, and also was accompanied by a significant increase in the activity of cytolysis markers in the serum, which significantly and negatively correlated with the activity of CSE and H2S in organs. Thus, formation of H2S deficiency due to simvastatin intake is probably one of the molecular mechanisms for the realization of hepato- and myotoxicity of this drug.