Sertraline is an (SSRI-)antidepressant metabolized by the polymorphic CYP2C19 enzyme. The aim of this study was to investigate the impact of CYP2C19 genotype on the serum concentrations of sertraline in a large patient population. Second, the proportions of patients in the various CYP2C19 genotype-defined subgroups obtaining serum concentrations outside the therapeutic range of sertraline were assessed. A total of 2190 sertraline serum concentration measurements from 1202 patients were included retrospectively from the drug monitoring database at Diakonhjemmet Hospital in Oslo. The patients were divided into CYP2C19 genotype-predicted phenotype subgroups, i.e. normal (NMs), ultra rapid (UMs), intermediate (IMs), and poor metabolisers (PMs). The differences in dose-harmonized serum concentrations of sertraline and N-desmethylsertraline-to-sertraline metabolic ratio were compared between the subgroups, with CYP2C19 NMs set as reference. The patient proportions outside the therapeutic concentration range were also compared between the subgroups with NMs defined as reference. Compared with the CYP2C19 NMs, the sertraline serum concentration was increased 1.38-fold (95% CI 1.26-1.50) and 2.68-fold (95% CI 2.16-3.31) in CYP2C19 IMs and PMs, respectively (p < 0.001), while only a marginally lower serum concentration (-10%) was observed in CYP2C19 UMs (p = 0.012). The odds ratio for having a sertraline concentration above the therapeutic reference range was 1.97 (95% CI 1.21-3.21, p = 0.064) and 8.69 (95% CI 3.88-19.19, p < 0.001) higher for IMs and PMs vs. NMs, respectively. CYP2C19 IMs and PMs obtain significantly higher serum concentrations of sertraline than NMs. Based on the relative differences in serum concentrations compared to NMs, dose reductions of 60% and 25% should be considered in PMs and IMs, respectively, to reduce the risk of sertraline overexposure in these patients.