Background: Clozapine is an antipsychotic with superior efficacy for treatment resistant schizophrenia, and has unique anti-suicidal properties and a low propensity to cause extrapyramidal side-effects. Despite these advantages, clozapine causes a number of potentially lethal side effects. Psychiatric nurses play a crucial role in management of psychiatric patient's undertaken clozapine Aim: This study aimed explore the relationship between psychiatric nurses' knowledge and practice toward side effects of clozapine drug on co-morbid psychiatric patients. Design: Descriptive co-relational design was used for this study. Subjects: comprehensive sample includes all psychiatric nurses (100) working in Port-said psychiatric and mental health hospital. Tools of data collection: The data was gathered through a self-administered questionnaire where the tools were divided into two parts: first part includes personal characteristics and professional background and second part includes two tools: Psychiatric nurse's knowledge regarding clozapine and its side effects and Psychiatric nurse's practice regarding clozapine and its side effects. Results: Psychiatric nurses obtained unsatisfactory knowledge regarding clozapine drug administration and management of side effects. However, psychiatric nurses obtained satisfactory practice level regarding clozapine drug administration and management of side effects. In addition, there was a positive significant correlation between psychiatric nurse's knowledge and practice regarding clozapine. Conclusion: There is a wide gap between psychiatric nurse's knowledge and their practice regarding clozapine administration and management of side effects on co-morbid psychiatric patients. Recommendations: Updating knowledge of psychiatric nurses regarding clozapine drug administration and management of side effects at undergraduate education and through educational packages at the service level.