Aim Comorbidity of pain and depression or anxiety is a challenging clinical phenomenon, often requiring the concurrent application of antidepressant and analgesic drugs. Growing evidence suggests that the analgesic metamizole exhibits cytochrome P450 inducing properties. In the present study, we assessed the impact of metamizole and ibuprofen on plasma concentrations of the selective serotonin reuptake inhibitor sertraline. Methods Out of a therapeutic drug monitoring (TDM) database, three groups of patients were compared: patients receiving sertraline and metamizole (n = 15), patients receiving sertraline and ibuprofen (n = 19), and a matched control group without one of the analgesics (n = 19). Results Metamizole was associated with 67% lower median sertraline plasma concentrations compared to the control group (14vs42 ng/mL,P< 0.001). In contrast, differences between the ibuprofen group and the control group did not reach statistical significance (31vs42 ng/mL,P= 0.128). Moreover, the metamizole group demonstrated lower dose-adjusted drug concentrations than the ibuprofen group (0.10vs0.26 (ng/mL)/(mg/day),P= 0.008). Finally, the metamizole group exhibited a higher proportion of patients whose sertraline concentrations were below the therapeutic reference range (40% in the metamizole group, 5% in the ibuprofen group, 0% in the control group,P= 0.005) indicating therapeutically insufficient drug concentrations. Conclusion Our findings support preliminary evidence that metamizole acts as a potent inductor of cytochrome P450 isoenzymes CYP2B6 and CYP3A4. We observed a clinically meaningful pharmacokinetic interaction between metamizole and sertraline, leading to insufficiently low sertraline drug concentrations. Clinicians should therefore consider alternative drug combinations or apply TDM-guided dose adjustment of sertraline.