BACKGROUND: The Northern Territory (NT) of Australia is currently experiencing a syphilis epidemic. Neurosyphilis is commonly considered in the differential diagnosis for patients presenting with neurologic conditions such as dementia and stroke in the NT. AIMS: To explore the local epidemiologic, diagnostic and treatment complexities of neurosyphilis in the NT and produce a guideline for clinical practice. METHODS: A database search was undertaken and local and global neurosyphilis guidelines were analysed. A guideline was created based on findings of the critical review and consultation with local multi-disciplinary experts. RESULTS: Neurosyphilis is frequently encountered in the NT but studies suggest it is often under-treated. Dementia is the most common clinical presentation locally. Establishing a diagnosis of neurosyphilis is complex and requires stepwise evaluation of clinical, laboratory and radiological findings. CONCLUSIONS: A clinical guideline and algorithm have been developed for the diagnosis and management of patients with neurosyphilis. This article is protected by copyright. All rights reserved.