Background <p>Bladder urothelial carcinoma (UC) represents a prevalent and clinically aggressive malignancy. For cisplatin-intolerant patients, there remains an urgent need to investigate alternative therapeutic regimens. This case report describes the application of combined immunotherapy and HER2-targeted antibody–drug conjugate (ADC) therapy in a patient with gemcitabine plus cisplatin (GC regimen) intolerant bladder UC.</p> Case presentation <p>A 66-year-old female patient was diagnosed with human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry 2+/3+) bladder UC (T3N0M0). Initial gemcitabine-cisplatin chemotherapy was discontinued due to severe adverse effects. The patient subsequently received four cycles of tislelizumab, an anti-programmed cell death protein-1 monoclonal antibody and five cycles of disitamab vedotin, a HER2-targeted ADC, as neoadjuvant therapy. The treatment was well tolerated, with mild adverse events. Following treatment, the patient underwent laparoscopic radical cystectomy with ileal neobladder reconstruction. The pathological diagnosis revealed treatment-related changes consistent with pathological complete response (pCR), with no recurrence observed during the 9-month postoperative follow-up.</p> Conclusion <p>This case demonstrates that neoadjuvant immunotherapy combined with HER2-targeted ADC therapy achieved pCR with a favourable safety profile in a GC regimen-intolerant patient with HER2-positive bladder UC. This result supports the further evaluation of this approach in both clinical studies and real-world practice.</p>