Patients with unresectable biliary tract cancer (uBTC) who progress despite first-line gemcitabine plus cisplatin (GC) treatment have limited systemic options with a modest survival benefit. Data are lacking on the clinical effectiveness and safety of personalized treatment based on multidisciplinary discussion for patients with progressing uBTC. This retrospective single-center study included patients with progressive uBTC who received either best supportive care or personalized treatment based on multidisciplinary discussion, including minimally invasive, image-guided procedures (MIT); FOLFIRI; or both (MIT and FOLFIRI), between 2011 and 2021. Ninety-seven patients with progressive uBTC were identified. Patients received best supportive care ( = 50, 52%), MIT ( = 14, 14%), FOLFIRI ( = 19, 20%), or both ( = 14, 14%). Survival after disease progression was better in patients who received MIT (8.8 months; 95% CI: 2.60-15.08), FOLFIRI (6 months; 95% CI: 3.30-8.72), or both (15.1 months; 95% CI: 3.66-26.50) than in patients receiving BSC (0.36 months; 95% CI: 0.00-1.24, < 0.001). The most common (>10%) grade 3-5 adverse events were anemia (25%) and thrombocytopenia (11%). Multidisciplinary discussion is critical for identifying patients with progressive uBTC who might benefit the most from MIT, FOLFIRI, or both. The safety profile was consistent with previous reports.