Background: Statins are the cornerstone of therapy in patients with hyperlipidemia. In high risk patients statins are employed for aggressive therapy, however part of the users are intolerant to these drugs. The aim of this study was to analyze the undesirable effects of moderate, median and high doses of rosuvastatin in CD-1 male mice that received a cholesterol-rich diet, focusing in the morphological and functional changes on hepatocyte mitochondria. Methods: We studied in a mouse model the combined administration of a cholesterol-rich diet (HD) along with a moderate high dose of rosuvastatin (Ro): 1, 2.5 or 5 mg/Kg/day during several days. Animals (n=6) were sacrificed, the liver mitochondria were isolated for analysis of respiratory function and microscopic studies. The respiratory control (state 3/state 4) and the O2 expenditure (nanoatoms/min/mg proteins) were evaluated. Results: Rosuvastatin doses higher than 20 mg/Kg/day induced premature death in hypercholesterolemic mice but not in mice with a cholesterol-free diet. Doses from 2.5 to 5 mg/Kg/day also induced morphological and functional alterations in mitochondria but the hypercholesterolemic animals survived longer. A dose of 1 mg/Kg/day, which is close to the maximal therapeutic dose employed in humans, did not affect mitochondrial architecture or respiratory function after two months of treatment. We analyzed the effect of rosuvastatin on the hepatic tissue where statins are most retained after their administration, and the main site of endogenous cholesterol synthesis. Conclusions: Our results contribute to understand the undesirable side effects of rosuvastatin in hypercholesterolemic mice, effects that can also be present in human being intolerant to statins.