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Background/Objectives: Interindividual variability in statin pharmacokinetics and susceptibility to statin-associated myopathy has been partly attributed to genetic variation in drug transporter genes. Polymorphisms in SLCO1B1 and ABCB1 influence statin disposition; however, their combined associations with systemic exposure and clinically relevant muscle toxicity remain incompletely characterized in routine clinical practice. This study aimed to investigate the association between common SLCO1B1 and ABCB1 gene polymorphisms, statin exposure, and muscle toxicity in statin-treated patients. Methods: In this prospective cohort study, 110 adult patients receiving atorvastatin or simvastatin were genotyped for SLCO1B1 rs4149056 and ABCB1 rs1045642. A representative subset of 40 participants underwent intensive pharmacokinetic evaluation. Muscle toxicity was assessed over a six-month follow-up period. Multivariable logistic regression analysis was performed to identify independent predictors of statin-associated myopathy. Results: Carriers of the SLCO1B1 rs4149056 C allele exhibited significantly higher systemic statin exposure, reflected by increased C_max and AUC_0–24 values. Statin-associated myopathy occurred in 8 participants (7.3%) and was significantly more frequent among SLCO1B1 CC genotype carriers. In multivariable analysis, the SLCO1B1 CC genotype was the strongest independent predictor of myopathy (OR 9.4, 95% CI 3.2–27.4), while the ABCB1 TT genotype and higher statin dose were also independently associated with increased risk. Conclusions: Genetic polymorphisms in drug transporter genes, particularly SLCO1B1, significantly influence statin exposure and muscle toxicity. These findings support the role of transporter-guided personalized statin therapy to improve treatment safety.