BACKGROUND: The efficacy of 5-aminosalicylic acid (5-ASA) in combination with advanced therapies (ADTs), particularly ustekinumab (UST), for the treatment of inflammatory bowel disease (IBD) remains unclear. METHODS: This retrospective cohort analysis used data from the Medical Data Vision database, including patients with ulcerative colitis (UC) and Crohn's disease (CD) who had initiated UST therapy. Cumulative UST continuation rates and factors associated with UST failure were analyzed, and post hoc subgroup analyses based on prior ADT use were conducted. RESULTS: A total of 1971 patients with CD and 1284 patients with UC were included. Overall, the concomitant use of 5-ASA did not significantly affect UST failure in either CD or UC. Post hoc subgroup analysis suggested a protective effect of 5-ASA in ADT-naive patients with CD or UC who had been previously exposed to ADT. CONCLUSIONS: 5-ASA did not provide a significant overall benefit when used in combination with UST for CD or UC. However, post hoc subgroup analyses indicated a potential role for 5-ASA in specific subgroups. Further studies are necessary to confirm these findings and explore personalized treatment strategies.