Introduction: Polypharmacy is a common clinical problem with many chronic diseases and can be associated with adverse patient outcomes. The present study aimed to determine patient-specific characteristics associated with polypharmacy in an ulcerative colitis (UC) population and to assess the impact of polypharmacy on disease outcomes. Methods: A retrospective chart review of patients with UC who visited a tertiary medical center outpatient clinics from 2004 to 2016 was performed. Patient demographics, medical and surgical histories, medications, and treatment histories were retrieved from the electronic medical record. Polypharmacy was defined as major (use of ≥ 5 non-UC medications) or minor (use of 2-4 non-UC medications). Both prescription and over-the-counter medications were included. Outcomes of interest include disease flare, therapy escalation, IBD-related hospitalization and surgery within 5 years of their initial visit. Results: 457 out of 498 patients with UC were eligible for baseline analysis. Major polypharmacy was identified in 29.8% of patients and minor polypharmacy represented 40.9% of the population. Polypharmacy at baseline was associated with increasing age (p<0.01), female gender (p=0.019), functional GI disorders (p<0.01), and psychiatric disease (p<0.01). Neither smoking nor alcohol usage was associated with polypharmacy. Over 5 years of follow up, 265 out of 457 remained eligible for analysis. After adjusting for age, gender, functional GI disorders, and psychiatric disease, major polypharmacy was significantly associated with increased risk of disease flare (odds ratio= 3.80, 95% confidence interval: 1.57-9.20). Polypharmacy was not associated with therapy escalation, IBD-related hospitalization or surgery. Further analysis on specific medication categories showed that baseline usage of narcotic pain medication was associated with increased risk of hospitalization (odds ratio= 3.84, 95% confidence interval: 1.09-13.57), whereas antidepressants, benzodiazepines, prebiotics or probiotics usage at baseline were not associated with any of the disease outcome measurements. Conclusion: Polypharmacy was present in a substantial proportion of patients with UC. Major polypharmacy was associated with increasing age, female gender, functional GI disorders, and concomitant psychiatric disease. Major polypharmacy may represent an independent risk factor for disease flare.