BACKGROUND: Treatment options for patients with refractory inflammatory bowel disease (IBD) or concomitant IBD and extraintestinal manifestations (EIM) are often limited. OBJECTIVE: This study aimed to examine the efficacy and safety of combining biologics or small molecules in patients with refractory IBD, active EIM, or active immune-mediated inflammatory disease (IMID). DESIGN: This was a retrospective and multicenter study. METHODS: We retrospectively collected demographics and disease characteristics from 47 patients with IBD who received dual-targeted therapy in 3 hospitals from January 2022 to June 2024. The primary endpoint was clinical remission based on the Harvey-Bradshaw index or patient-reported outcome 2 after at least 4 months of combination therapy. The secondary endpoints included clinical response, endoscopic response, and endoscopic remission, as well as all adverse events that occurred within the period of combination therapy. RESULTS: In total, 47 IBD patients including 37 with refractory IBD, 5 with active EIM, and 5 with active IMID received dual-targeted therapy, of which 37 achieved clinical response (78.7%) and 27 achieved clinical remission (57.4%) at a median follow-up time of 13.0 months. Among these 47 patients, 29 patients underwent endoscopic follow-up, of which 15 (51.7%) achieved endoscopic response and 8 (27.6%) achieved endoscopic remission at a median follow-up time of 9.0 months. Mild and moderate adverse events were reported in 17 (36.2%) patients within the period of combination therapy, and serious adverse events requiring hospitalization occurred in 1 patient (2.1%). CONCLUSION: The combination therapy of biologics and small molecules for refractory IBD or those with concomitant EIM/IMID is effective and safe.