In the psychiatric setting, therapeutic drug monitoring and genotyping for cytochrome P450 (CYP) polymorphisms help to ensure and maintain therapeutic drug levels. In this study, the authors extended the therapeutic drug monitoring and genotyping protocol routinely used in their psychiatric clinic to primary care patients treated with antidepressants. They examined the variation in serum concentrations and assessed the role of CYP polymorphisms, wrong dosing, and noncompliance in deviating serum concentrations. Of 227 serum concentrations obtained, 127 (56%) were more than 20% outside therapeutic ranges. Of these 127 cases, 64 (50%) were congruous with aberrant CYP2D6 or CYP2C19 genotypes, incorrect dosing, or a pharmacy record suggesting noncompliance. Prevalence of aberrant CYP2D6 and CYP2C19 genotypes did not differ significantly between the investigated primary care patients and 751 secondary care users of antidepressants. The therapeutic drug monitoring and the genotyping findings resulted in recommendations to physicians to alter the medication strategy of 146 (64%) patients. These results strongly suggest that the rationale for therapeutic drug monitoring and CYP genotyping when prescribing antidepressants in secondary care also applies to the primary care setting.