Background Although comorbidity of substance use and psychotic disorders can lead to increase in morbidity and mortality, less is known about the prevalence and predictors. Patients with psychosis tend to be overlooked during clinical assessment, therefore, the possibility of a missed or undertreated condition such as substance use increases. This study aims to measure the prevalence of substance use in patients with psychosis and to assess the strongest predictors.Method In a 1 year observational study (October 2017- November 2018), 311 patients with psychosis who were admitted to Razi Psychiatry Hospital; Tehran; Iran were surveyed through The Structured Interview Based on DSM-5 (SCID) for diagnostic confirmation as well as questions assessing prevalence and possible predictors of substance use.Results Prevalence of Substance Use among Psychiatric Patients with Psychosis was 37.9%. In bivariate analysis, several variables were identified as factors correlated with drug abuse among the participants. These included younger age, male gender, being currently homeless, having family history of drug use, and a history of imprisonment. The most powerful predictor of substance use, however, were male gender, Family history of drug use and being currently homelessness.Conclusion The prevalence of substance use was high among all psychotic disorders, therefore, it is suggested that professionals note the importance of substance use among psychotic patients. The most powerful predictors were male gender, history of imprisonment, and family history of drug use. Active investigation and comprehensive preventive plans are suggested in all patients with psychosis especially among high risk population.