Schizophrenia is a chronic mental disorder and one of the main causes of disability in the world. Approximately 1% of the general population suffers from this disorder, and almost 30% of cases are unresponsive to antipsychotic therapies. Clozapine is a Food and Drug Administration (FDA)-approved antipsychotic drug for treatment-resistant schizophrenia (TRS). Clozapine is also approved for the prevention of suicide associated with schizophrenia. However, clozapine is not the preferred first-line medication because of its potential AEs, including agranulocytosis, metabolic syndromes, and myocarditis. Clozapine prescription requires weekly absolute neutrophil count (ANC) monitoring for the first six months, followed by biweekly monitoring until the patient has finished one year of treatment. Several psychiatric disorders have been reported to be associated with inflammatory biomarkers. Dysregulation of the immune system and the elevation of pro-inflammatory cytokines were also reported to be associated with schizophrenia, highlighting the necessity of further research into the etiology of the disease and the relationship between the immune system and clozapine-responsiveness to support better management of symptoms and potential AEs. In this framework, we searched PubMed using the medical subject headings (MeSH) terms "clozapine", "antipsychotics", "schizophrenia", "treatment-resistant schizophrenia", "immune system", "inflammation", "neuroinflammation", "biomarker", "cytokine", and "chemokine" with the aim of overview the impact of clozapine on the immune system in individuals with treatment-responsive and treatment-resistant schizophrenia.