The antidepressant vortioxetine is primarily metabolised by the polymorphic enzyme CYP2D6. The objective of this study was to investigate the effect of CYP2D6 genotype on exposure and therapeutic failure of vortioxetine. The analysis included data from CYP2D6-genotyped patients (N=458) on vortioxetine treatment from a Norwegian therapeutic drug monitoring database. Compared with CYP2D6 normal metabolizers (NMs; N=242), vortioxetine exposure was 3.0-fold (p<0.001) increased in poor metabolizers (PMs; N=35), 1.5-fold (p<0.001) increased in intermediate metabolizers (IMs; N=173), and not significantly changed (p=0.21) in ultra-rapid metabolizers (UMs; N=8). Compared with NMs, treatment switch from vortioxetine to alternative antidepressants was 8.0-fold (95%CI: 2.0-32.3, p=0.001) more frequent among PMs and 12.7-fold (95%CI: 1.1-94.9, p=0.02) more frequent among the CYP2D6 UMs. In conclusion, CYP2D6 genotype was associated with significant changes in vortioxetine exposure and may also be associated with risk of therapeutic failure.