ABSTRACT Background Cannabis use and Psychosis are closely associated. Polysubstance use is prevalent among cannabis users. However, previous literature majorly examined the relationship between only cannabis use and schizophrenia disorder. Little is known about the impact of polysubstance use on the onset of prodromal symptoms. There is a scarcity of studies comparing the severity and characteristics of prodromal symptoms between cannabis users and polysubstance users. Aim This study investigates the association between polysubstance use and prodromal symptoms. It also compares the severity and characteristics of prodromal symptoms among individuals with different substance use patterns. Method 246 first-degree relatives of patients with schizophrenia participated in the study, using purposive sampling method. Pattern of substance use and prodromal symptoms were assessed using the WHO ASSIST Scale and PROD-Screen respectively. Result Significant association was found between substance use and symptoms of prodrome (r = −0.57, p < .01). Individuals who consumed more than one substance experienced more severe prodromal symptoms. Prodromal symptoms viz. “hallucinatory and delusional symptoms” and affect and thinking difficulties discriminate the study groups effectively. Conclusion Cannabis plus other substance use increases the risk of prodrome among first-degree relatives of patients with schizophrenia. Polysubstance use causes more thinking, affective, delusionary, and hallucinatory symptoms of prodrome.