Abstract BACKGROUND Common first-line treatments for ulcerative colitis (UC) currently include anti-tumor necrosis factor (anti-TNF) agents, ustekinumab (interleukin-12/interleukin-23 receptor antagonist), and vedolizumab (integrin antagonist). However, there are safety concerns when prescribing biologic therapies to elderly patients. While these medications have all demonstrated general efficacy and safety in UC, this study aims to examine the long-term comparative safety of anti-TNF agents with vedolizumab and ustekinumab in elderly patients with UC. METHODS The Research Network on TriNetX database was accessed on September 26, 2023, to identify patients at least 65 old who were diagnosed with UC: the first cohort included patients prescribed anti-TNF agents (included adalimumab, certolizumab pegol, golimumab, and infliximab) and the second cohort included patients prescribed either vedolizumab or ustekinumab. Primary outcomes included mortality, corticosteroid use, subsequent colectomy, colon cancer, infections, and all-cause hospitalizations within 10 years after matching for age, sex, and race. All analyses were performed in real-time using built-in statistical algorithms on TriNetX. RESULTS After matching cohorts, 1,075 elderly patients with UC patients were included in each cohort as shown in table 1. Patients who were prescribed anti-TNF therapy had a significantly increased 10-year risk of mortality (10.7%) compared to patients on either vedolizumab or ustekinumab therapy (5.77%) (OR 1.96, 95% CI [1.42, 2.7], p <0.0001). Corticosteroid use was higher in the anti-TNF cohort (40.6% vs 34.9%, p= 0.007). There were no significant differences between the two cohorts when comparing the need for colectomy (3.26% vs 2.23%, p = 0.15) or colorectal cancer occurrence (1.67% vs 2.05%, p=0.52) within 10 years. However, the anti-TNF cohort had a higher risk of all-cause hospitalization (32.5 % vs 22%, p=<0.0001), respiratory tract infections (18.4% vs 14.5%, p=0.015), and urinary tract infections (10.4% vs 7%, p=0.005). CONCLUSION In elderly patients with UC, ustekinumab or vedolizumab are safer treatment options compared to anti-TNF therapy. Table 1 Demographics and Comparative 10-year Outcomes of Elderly Patients with UC.