Objective: The aims of the present study were to derive and validate a clinical decision rule (CDR) to rule out the need for computed tomography of the brain (CTB) in nontraumatic patients who present to the ED. Methods: This is a retrospective review of non-traumatic patients who presented to the EDs in two urban hospitals and received CTB from January 2014 to December 2016. Data from one hospital were used to develop a CDR for clinically significant CTB findings. Clinically significant CTB findings were defined as acute infarction, intracranial neoplasm, intracranial haemorrhage, acute hydrocephalus, cerebral oedema and intracranial infection. Patients from another hospital were used as a validation cohort to evaluate the CDR and compare it to four previously derived CDRs.Results: There were 5296 cases in the derivation cohort, with 345 (6.5%) clinically significant CTB findings. Identified risk factors were: focal neurological deficit (adjusted odds ratio [OR] 3.4, 95% confidence interval [CI] 2.6-4.4), Glasgow Coma Scale <15 (adjusted OR 3.5, 95% CI 2.6-4.6), history of malignancy (adjusted OR 3.2, 95% CI 2.4-4.2), nausea and/or vomiting (adjusted OR 1.6, 95% CI 1.1-2.1), headache (adjusted OR 1.1, 95% CI 0.9-1.5) and coagulopathy (adjusted OR 9.2, 95% CI 2.1-41.5). These criteria and four pre-existing CDRs were applied to the validation cohort of 5098 patients from the second hospital, which had 338 (6.6%) clinically significant CTB findings. Our criteria were found to have a sensitivity of 99.7% (95% CI 99.1-100.0) and a specificity of 11.0% (95% CI 10.1-11.9). The risk of having a clinically significant CTB finding is 0.3% if patients do not meet any of the criteria. Conclusion: The CDR derived in the present study achieved the highest sensitivity and a moderate specificity when compared with four other pre-existing CDRs for nontraumatic brain injury patients.• Create a useful CDR for clinicians to identify low-risk patients for non-traumatic brain injury. • Hence decrease harmful, costly, over-scanning of patients with CT brain.