OBJECTIVES: Polypharmacy is very common in patients with schizophrenia. Risperidone is a commonly used antipsychotic that is metabolized primarily by CYP2D6 and CYP3A4 in the liver. There is a risk of drug-drug interactions with medications that inhibit or induce these enzymes, which may affect clinical outcomes in schizophrenic patients. This study aims to explore and quantify the association between exposure to inhibitors and/or inducers of CYP3A4 and CYP2D6 and the risk of discontinuation of risperidone in patients with schizophrenia. METHODS: A nested case-control study was conducted using administrative claims data. Patients were 16-years or older with a diagnosis of schizophrenia and at least two successive claims for risperidone. Cases were patients that discontinued risperidone. Ten controls were randomly chosen for each case, matching on time on treatment. For each case-control set, exposure was defined as use of an inhibitor or inducer in the one-month, three months and six months prior to the case time. The association between exposure and the risk of discontinuation of risperidone was measured using conditional logistic regression models. RESULTS: The base cohort included 20,840 patients and 10,913 cases were identified. Exposure to inhibitors was associated with an increased risk of discontinuation in the three- and six-month exposure windows (OR: 1.10 (1.06–1.14) and 1.11 (1.07–1.15), respectively). The association was stronger for exposures occurring when patients were new to treatment with risperidone. For instance, the OR for exposure to an inhibitor in the last three months was 1.16 (1.00-1.33) during the first month of treatment compared with 1.09 (1.00-1.19) by six months of treatment. CONCLUSION: Co-medication with an inhibitor of CYP2D6 or CYP3A4 is associated with a greater risk of discontinuation of risperidone, which may have negative implications for clinical outcomes in schizophrenia.