OBJECTIVES: There are high rates of polypharmacy with antipsychotic medications. Antipsychotic drugs are mainly metabolized by the cytochrome system; risperidone is primarily metabolized by CYP3A4 and CYP2D6, quetiapine by CYP3A4, and olanzapine by CYP1A2. There are many commonly used medications that may inhibit or induce metabolism via these enzyme systems. There is therefore a risk of drug-drug interactions (DDIs) when these medications are taken concomitantly. The objective of this study was to describe the rates of co-medication with antipsychotics that may lead to DDIs in Ontario, Canada. METHODS: A retrospective analysis of claims data was conducted from March 2006 – February 2007 using data obtained from Brogan Inc. Inhibitors and inducers of the major metabolic enzymes of risperidone (CYP2D6 and CYP3A4), quetiapine (CYP3A4) and olanzapine (CYP1A2) were identified using published literature and drug information sources. The prevalence of co-medication with risperidone, quetiapine and olanzapine and respective inducers and inhibitors of CYP2D6 and CYP3A4, CYP3A4 alone and CYP1A2 alone was described. RESULTS: 57.5% of claims for risperidone overlapped at least 25% with claims with one or more inhibitor or inducer of CYP3A4 or 2D6. Similarly, 43.9% of quetiapine claims overlapped with one or more inhibitor/inducer of CYP3A4, and 24.0% of olanzapine claims for one or more inhibitor/inducer of CYP1A2. The most commonly overlapping inhibitor/inducer with risperidone were selective serotonin reuptake inhibitors (SSRIs; 22.7% of claims). SSRIs that interacted with CYP1A2 were also the most commonly used co-medication with olanzapine (7.8%), while gastrointestinal acid suppression agents were the most common inhibitor/inducer with quetiapine (9.7%). CONCLUSION: A high percentage of Ontario drug benefit beneficiaries were prescribed both an atypical antipsychotic and a medication that may interfere with its metabolism. This may have implications for untoward clinical outcomes such as adverse effects or exacerbation of illness.