Background and hypothesis: Schizophrenia and comorbid substance use disorders (SUDs) are associated with poor treatment outcomes but differences between the associations of different SUDs with clinical outcomes are poorly characterized. This study examines the associations of comorbid SUDs with clinical outcomes in schizophrenia using a largescale electronic health record (EHR) database. Design: Real-world data (RWD) analysis using the NeuroBlu database; de-identified EHR data were analysed. Multivariable logistic regression, Poisson and CoxPH models were used to compare the associations of specific comorbid SUDs with outcome variables. Results: Comorbid SUD was significantly different on all outcome measures compared to no SUD (U = 1.44e 7–1.81e 7, all ps < .001), except number of unique antipsychotics (U = 1.61e 7, p = .43). Cannabis (OR = 1.58, p < .001) and polysubstance (OR = 1.22, p = .007) use disorders were associated with greater CGI-S. Cannabis (IRR = 1.13, p = .003) and polysubstance (IRR = 1.08, p = .003) use disorders were associated with greater number of unique antipsychotics prescribed, while cocaine (HR = 1.87, p < .001), stimulants (HR = 1.64, p = .024), and polysubstance (HR = 1.46, p < .001) use disorders were associated with a shorter time to antipsychotic discontinuation. Conversely, alcohol use (IRR = 0.83, p < .001), cocaine use (IRR = 0.61, p < .001), opioid use (IRR = 0.61, p < .001), stimulant use (IRR = 0.57, p < .001) and polysubstance use (IRR = 0.87, p < .001) disorders were associated fewer inpatient days. Conclusion: Comorbid SUDs were generally associated with greater CGI-S and poorer clinical outcomes in patients with schizophrenia. Treatment strategies should target not only schizophrenia symptoms but also comorbid SUD to improve management of both conditions.