Polysubstance Use (PSU), the use of two or more substances of abuse, has been associated with increased risk for development of psychiatric conditions and early death compared to both monosubstance use or no substance use. The vast majority of clinical research on prescription or recreational drug consumption in patients with inflammatory bowel disease (IBD), including both Crohn’s disease (CD) and ulcerative colitis (UC), has focused on use of individual substances. We evaluated the incidence and impact of PSU in IBD and assessed potential predisposing factors in this setting.