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Background/Objectives: Using a human liver donor bank, we previously demonstrated a strong correlation between donor history of ethanol consumption and increased hepatic CYP2B6 mRNA, protein, and enzymatic activity, suggesting that ethanol may enhance CYP2B6 expression in vivo. The objective of this study was to determine whether ethanol exposure increases CYP2B6 gene expression in hepatic and intestinal cell models commonly used to study cytochrome P450 induction, and to assess whether observed expression patterns are consistent with CAR- or PXR-related regulatory involvement. Methods: Human-derived hepatic (HepG2) and intestinal (Caco-2 and LS180) cell lines, as well as HepG2 cells stably expressing murine constitutive androstane receptor (HepG2-mCAR), were treated with ethanol. Phenobarbital (a CAR activator) and rifampin (a pregnane X receptor [PXR] activator) were used as reference inducers. CYP2B6, CYP2B7, and CYP2B6 splice variant (CYP2B6-SV2) mRNA expression levels were quantified by real-time RT-PCR. Results: Compared with vehicle control (0.5% DMSO), ethanol increased CYP2B6 mRNA expression by 35-fold (P = 0.026) in HepG2-mCAR cells and 27-fold (P = 0.002) in Caco-2 cells, but produced no significant change in HepG2 or LS180 cells. Phenobarbital produced similar but smaller increases in CAR-responsive models, whereas rifampin selectively induced CYP2B6 in LS180 cells. Ethanol and phenobarbital also increased CYP2B7 mRNA expression, while transcript levels of the splice variant CYP2B6-SV2 remained unchanged. Conclusions: Ethanol enhances CYP2B6 and CYP2B7 mRNA expression in hepatic and intestinal cell models, with expression patterns consistent with CAR-related regulatory involvement. These findings support a mechanistic basis for ethanol-associated modulation of CYP2B6 expression relevant to alcohol–drug interactions.