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Atorvastatin (ATV), is commonly used to treat hypercholesterolemia. Although generally well tolerated, patients can suffer from muscle complaints and the occurrence of this discomfort is difficult to predict. Muscle side effects are assumed to be linked to the intramuscular ATV accumulation. The aim of our study was to investigate the relative implication of influx and efflux transporters expressed in the muscle tissue (OATP2B1, MRP1) in promoting or limiting the access of the drug into the cells. In addition, the impact of common single nucleotide polymorphisms (SNPs) in SLCO2B1 coding for OATP2B1 (rs12422149; c.935G > A) and in ABCC1 coding for MRP1 (rs45511401; c.2012G > T) was evaluated. Single or double transfectant HEK293 recombinant models overexpressing variant or wild-type OATP2B1 (influx) and/or MRP1 (efflux) proteins were developed. Our results confirm the implication of both OATP2B1 and MRP1 in ATV transport. Interestingly, ATV intracellular accumulation promoted by OATP2B1 influx was counteracted by MRP1 efflux. The c.935G > A SNP in SLCO2B1 was associated with a decreased OATP2B1 influx activity whereas the c.2012G > T SNP in ABCC1 appeared to increase MRP1 efflux activity towards ATV. In conclusion, intracellular ATV accumulation is regulated by transporter proteins and their functionality could play a role in ATV muscle side effect susceptibility.