Background Distinguishing between substance-induced psychosis (SIP) and primary psychosis is crucial for understanding illness and providing optimal treatment. Substance use is widespread and causes concern for many reasons, particularly the psychotogenic properties of many substances. Aim The purpose of this study was to differentiate SIP from primary psychosis. Patients and methods A cross-sectional comparative study on 100 patients of both genders who were divided into two groups: group I included those with SIP and group II included those with primary psychosis; 18–65 years old was collected from the Neuropsychiatry Department, Tanta University and from the Centre of Psychiatry, Neurology and Neurosurgery. The study was conducted from July 2016 to July 2017. Psychosis was assessed by positive and negative syndrome scale. Arabic version of the addiction severity index was used to assess the severity of addiction and drug screen of urine once the patient was admitted. Results There was a significantly older age among group II (primary psychosis) with a mean age of 34.540±10.017. There were more men in group I, all patients were men in group I. Group II shows significantly more unemployed patients (45 patients, 90%). Unmarried patients were significantly more among group II. There were more patients with a family history of addiction among group I (35 patients, 70%) and more patients with a family history of psychiatric disorders among group II (30 patients, 60%). The number of patients presented with visual hallucination was higher among group I (33 patients, 66%). The number of patients presented by negative symptoms in group II was higher (42 patients, 84%). The total score of positive and negative syndrome scale was higher among group II. Conclusion There is a great difference between SIP and primary psychosis.