CYP2D6 genetic polymorphisms are considered a major contributor to the large inter-individual variability in CYP2D6-mediated drug metabolism, but fail to explain significant portion of the variability. The aim of this study was to assess the ability of CYP2D6 activity score (AS) estimated from CYP2D6 genotype to predict CYP2D6 expression and enzyme activity. The CYP2D6 gene region was sequenced in 115 healthy human liver tissue samples to determine their CYP2D6 AS. Additionally, CYP2D6 enzyme activity, protein, and mRNA levels were estimated. CYP2D6 AS explained 23% of the inter-individual variability in CYP2D6 activity, but only 7.5% in tissues assigned AS 1-2. CYP2D6 protein level was found to be the major determinant of CYP2D6 activity, explaining 59% of variability. These findings suggest that while CYP2D6 AS is a good predictor of poor metabolizer phenotype, additional non-genetic factors may govern the rate of CYP2D6-mediated metabolism in those without the poor metabolizer phenotype. This article is protected by copyright. All rights reserved.