Results: By combining extensive insecticide bioassays with and without addition of the synergist PBO, and gene copy number and expression quantification of two key P450 enzymes (CYP6CY3 and CYP6CY4) in a 23 clone collection, we, (i) confirmed that metabolic resistance is correlated with P450 expression level, up to a threshold, (ii) demonstrated that the R81T mutation, in the homozygous state and in combination with P450 overexpression, leads to high levels of resistance to neonicotinoids, and, (iii) showed that there is a synergistic interaction between the P450 and R81T mechanisms, and that this interaction has the strongest impact on the strength of resistance phenotypes. However, even though the R81T mutation has a great effect on the resistance phenotype, different R81T genotypes can exhibit variation in the level of resistance, explained only partially by P450 overexpression. Conclusion: comprehend resistance phenotypes, it is important to take into account every mechanism at play, as well as the way these mechanisms interact.