Background <p>Intolerance to 5-aminosalicylic acid (5-ASA) is linked to poorer outcomes in ulcerative colitis (UC), but its impact on progression to difficult-to-treat (D2T) disease and the contribution of specific intolerance phenotypes remain uncertain. We evaluated the long-term prognostic impact of 5-ASA intolerance phenotypes and post-intolerance treatment status.</p> Methods <p>This retrospective cohort study included 919 patients with UC. Cumulative incidence functions were compared using Gray’s test, treating death and colectomy as competing events when assessing progression to D2T. Multivariable models were adjusted for baseline covariates and immunomodulator use. Landmark analyses and sensitivity analyses using secondary failure of ≥&#xa0;2 mechanisms of action after advanced therapy initiation were performed.</p> Results <p>Among 919 patients, 145 (15.8%) were classified as 5-ASA intolerant, including 83 with acute intolerance syndrome (AIS) and 62 with non-AIS phenotypes. Overall intolerance was independently associated with an increased risk of D2T progression (subdistribution hazard ratio [sHR] 2.07, 95% confidence interval [CI] 1.14–3.75), but not with colectomy. The excess risk was largely driven by AIS (sHR: 3.25, 95% CI: 1.64–6.45). Landmark analyses showed that 5-ASA users at 90 or 365&#xa0;days exhibited a lower cumulative incidence of D2T progression than non-users. Furthermore, following advanced therapy initiation, overall 5-ASA intolerance was not associated with secondary failure of ≥&#xa0;2 mechanisms of action, whereas AIS remained independently associated with this outcome.</p> Conclusions <p>Progression to D2T UC among patients with 5-ASA intolerance is largely attributable to AIS. Careful characterization of 5-ASA phenotype may improve risk stratification and inform individualized therapeutic strategies in UC management.</p>