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Intravenous thrombolysis (IVT) improves outcomes after acute ischemic stroke but is underused in certain patient populations. Mental illness is pervasive in the United States, and patients with comorbid psychiatric disease experience inequities in treatment for a range of conditions. We aimed to determine whether comorbid psychiatric disease is associated with differences in IVT use in acute ischemic stroke.Acute ischemic stroke admissions between 2007 and 2011 were identified in the Nationwide Inpatient Sample. Psychiatric disease was defined by International Classification of Diseases, Ninth Revision, Clinical Modification codes for secondary diagnoses of schizophrenia or other psychoses, bipolar disorder, depression, or anxiety. Using logistic regression, we tested the association between IVT and psychiatric disease, controlling for demographic, clinical, and hospital factors.Of the 325 009 ischemic stroke cases meeting inclusion criteria, 12.8% had any of the specified psychiatric comorbidities. IVT was used in 3.6% of those with, and 4.4% of those without, psychiatric disease (P<0.001). Presence of any psychiatric disease was associated with lower odds of receiving IVT (adjusted odds ratio, 0.80; 95% confidence interval, 0.76–0.85). When psychiatric diagnoses were analyzed separately individuals with schizophrenia or other psychoses, anxiety, or depression each had significantly lower odds of IVT compared to individuals without psychiatric disease.Acute ischemic stroke patients with comorbid psychiatric disease have significantly lower odds of IVT. Understanding barriers to IVT use in such patients may help in developing interventions to increase access to evidence-based stroke care.