Background In recent years, immunological hypotheses have gained momentum proposing that the immune system plays a critical role in the development of mental disorders in a subgroup of patients. Studies have shown that autoimmune mechanisms and infections increase the risk of mental disorders and also that some persons with mental disorders have increased levels of peripheral immune components. However, the role and presence of immunological abnormalities in the brain measured in the cerebrospinal fluid (CSF) is rather unclear since only few and smaller studies have investigated the CSF of individuals with mental disorders. Some studies suggested an increased permeability of the blood-brain barrier (BBB) in up to 53.3% of patients diagnosed with schizophrenia and also CSF levels of protein and albumin have been shown to be elevated in up to 42% of patients with schizophrenia and 22% of patients with depression. Elevated CSF levels of white blood cell counts, CSF Immunoglobulin-G (IgG) ratios and the presence of oligoclonal bands have also been reported. However, the CSF studies among patients with mental disorders conducted so far have been based on a limited number of cases, only few have included healthy control subjects and the studies have been performed rather unsystematically. By using the Danish registers, we will conduct the largest study to date investigating the role of inflammation in the brain in the development of mental disorders based on existing CSF samples. Methods The Clinical Laboratory Information System (LABKA) Research Database contains information on all CSF and blood tests performed during in- or outpatient hospital contacts in the North and Central Region of Denmark since 2000 until 2012. By using the unique CPR number assigned to every Danish citizen, we will identify individuals with increased levels of CSF cell count, IgG index, albumin CSF/plasma ratios, and individuals with the presence of oligoclonal bands in the CSF. These individuals will be linked to the Psychiatric Central Register for the assessment of psychiatric diagnoses. We will furthermore investigate the association in the opposite order, i.e. individuals with psychiatric diagnoses registered in the Psychiatric Central Register will be followed in the LABKA database for any of the mentioned abnormal CSF test results. The CSF test results will further be combined with the plasma levels of CRP and white blood cells in order to examine if signs of inflammation in the CSF and further in the blood gives an even stronger association between abnormal CSF test results and mental disorders. Data will be analysed using survival analysis techniques (Cox or Poisson regression analyses) and the incidence rate ratios (IRRs) will be used as an approximation of relative risk. Results Results are expected primo 2019 and are expected to be presented at the SIRS conference 2019. Discussion Due to the Danish registers we will be able to longitudinally investigate the associations between increased levels of inflammation and signs of blood-brain barrier dysfunction, and the development of mental disorders. We will also be able to investigate if individuals that are already diagnosed with a mental disorder have an increased risk of any of these CSF abnormalities. By using the LABKA database, we are able to conduct the largest CSF study so far and thereby contribute to the understanding of the associations between inflammatory mechanisms in the brain and the development of mental disorders.