Background: Efavirenz (EFV) is characterized by interindividual pharmacokinetic variability causing inconsistent clinical responses. Previous studies have identified some possible genetic determinants of the variability in plasma concentrations. However, their impact on EFV intracellular pharmacokinetics remains mostly unexplored. Aims: To confirm previous observations concerning the influence of genetic polymorphisms on EFV plasma concentrations and to assess their effect on the intracellular pharmacokinetics of EFV. Materials & methods: EFV concentrations in plasma ([EFV]_Cmin) and in peripheral blood mononuclear cells ([EFV]_CC) were determined in 50 HIV-infected patients. Subjects were genotyped for 13 polymorphisms in 5 different genes (CYP2A6, CYP2B6, CYP3A5, UGT2B7 and ABCB1). Relationships between genetic status and [EFV]_Cmin, [EFV]_CC or EFV accumulation in peripheral blood mononuclear cells (EFV accumulation ratio or accumulation ration [AR]) were then evaluated. Results: CYP2B6 allelic status was associated with differences in [EFV]_Cmin but also in [EFV]_CC. Patients carrying at least one mutated allele showed significantly higher [EFV]_Cmin and [EFV]_CC than homozygous wild-type (mutated homozygous [m/m] >heterozygous [wt/m]>homozygous wild-type [wt/wt], p<0.001). ABCB1 rs3842T>C was significantly associated with higher EFV AR (p = 0.032). Finally, the ABCB1 3435C>T SNP was associated with a lower increase in CD4-cell count after EFV therapy initiation. Conclusion: Our study corroborates previous findings indicating that knowledge of CYP2B6 genetic status should be taken into account for an EFV treatment. Our results also constitute the first demonstration of the significant influence of CYP2B6 genetic polymorphisms on [EFV]_CC and suggest that ABCB1 SNPs may also influence the clinical impact of EFV treatment.