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Introduction: Understanding the reasons for the wide variation in health care spending among patients with schizophrenia may benefit the development of interventions aimed at improving patient outcomes and health care spending efficiency. The aim of our study was to determine factors associated with high health care spending in the patient population., Methods: A serial cross-sectional study used the administrative health records of residents of Alberta, Canada between 1 January 2008 and 31 December 2017 and provincial costing methodologies to calculate total health care spending and sector-specific costs. Factors that modified the odds of being a high cost (i.e. 95th percentile or higher) patient with schizophrenia were estimated using generalized estimating equations., Results: This study captured 242 818 person-years of observations among 38 177 unique patients with schizophrenia. Increased odds of being a high-cost patient were associated with younger age (18-29 years), male sex, unstable housing status and requiring care from multiple medical specialties. The strongest estimated associations between high cost status and comorbidity were for metastatic cancer (OR = 2.26) and cirrhosis (OR = 2.07). In contrast, polypharmacy was associated with a decreased odds of being high cost compared with untreated patients., Conclusion: Factors associated with being a high-cost patient are the result of complex interactions between individual, structural and treatment-related factors. Efforts to improve patient outcomes and address rising health care costs must consider the value of allocating resources towards early detection and support of patients with schizophrenia along with the prevention/management of comorbidity., Competing Interests: None.