INTRODUCTION: 3-hydroxy-methylglutaryl-CoA (HMG-CoA) reductase inhibitors, statins, are effective drugs for blood cholesterol lowering and preventing of cardiovascular events. Numerous reports have confirmed that statins have a good safety profile, but some of the side effects occur in a small number of patients. OBJECTIVE: Our study aimed to evaluate the influence of gene polymorphisms of membrane transporters SLCO1B1, ABCB1 and ABCG2 and metabolic enzymes CYP2C9 and CYP2C19 on the occurrence of rosuvastatin-related myotoxicity and hepatotoxicity. METHODS: In a period of two years, 220 patients on rosuvastatin therapy were consecutively included in the study, of which 95 developed side effects (88 muscular, 6 hepatic, and 1 both), and 125 patients without side effects served as controls. In the multivariate regression model, the predictor variables defined by the hypotheses and goals (polymorphisms of the SLCO1B1, ABCB1, ABCG2, CYP2C9, CYP2C19 genes and the drug-drug-gene interaction) were analyzed, which in previous bivariate analyzes showed a significance level of P<0.200. RESULTS: Our results associate risk gene variants with the occurrence of rosuvastatin side effects: SLCO1B1 c.521 C>A (OR=2.52; 95% CI=1.42-4.48; P=0.002); ABCG2 c.421C>A (OR=2.68; 95% CI=1.28-5.60; P=0.008) and CYP2C9*2*3 (OR=2.40; 95% CI=1.15- 5.00; P=0.019). Our study is the first study that showed a significant influence of variant genotypes of the CYP2C9 gene on the occurrence of rosuvastatin myotoxicity. CONCLUSION: Loss-of-function polymorphisms in SLCO1B1 c.521T>C, ABCG2 c.421C>A and CYP2C9*2*3 genes are associated with rosuvastatin side effects.