Background and Aims <p>The role of 5-aminosalicylates (5-ASA) in maintaining remission in patients with ulcerative colitis (UC) receiving advanced therapy remains controversial. This study evaluated the safety and feasibility of 5-ASA discontinuation and dose reduction in patients with UC who achieved remission with advanced therapies.</p> Methods <p>This multicenter retrospective cohort study included patients with UC who achieved steroid-free clinical remission with advanced therapies at three centers (2010–2025). Patients were categorized into continuation or discontinuation groups based on 5-ASA status after achieving remission. The primary outcome was time to clinical relapse. Dose reduction versus dose maintenance was also evaluated among patients who continued 5-ASA.</p> Results <p>170 treatment episodes were analyzed: 153 in the continuation group and 17 in the discontinuation group. The relapse rate was 17.6% (3/17) in the discontinuation group and 18.3% (28/153) in the continuation group, with no significant difference in relapse-free survival (log-rank <i>P</i> = 0.597). Among continuers, 21 underwent dose reduction and 132 maintained their dose; dose reduction did not increase relapse risk (log-rank <i>P</i> = 0.273). Cox regression analysis showed 5-ASA discontinuation was not associated with increased relapse risk (HR: 0.719, 95% CI: 0.218–2.378, <i>P</i> = 0.589), with only prior advanced therapy exposure significantly predicting relapse.</p> Conclusion <p>This is the first real-world study evaluating 5-ASA discontinuation in patients with UC achieving remission with advanced therapies. Discontinuation or dose reduction of 5-ASA might not be associated with increased relapse risk in carefully selected patients. Although limited sample size restricts definitive conclusions, these findings suggest reducing medication burden may be feasible in selected patients.</p>