BackgroundPhase II trials showed the efficacy of anti-HER2 RC48-ADC (disitamab vedotin) for HER2-positive metastatic urothelial carcinoma (UC). This study evaluated RC48 alone verses in combination with immunotherapy for locally advanced or metastatic UC using real-world data.MethodsThis retrospective, multicenter, real-world study included patients with locally advanced or metastatic UC who received RC48 in five hospitals in China between July 2021 and April 2022. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events.ResultsThirty-six patients were included. The patients were 47–87 years, and 26 (72.2%) were male. Eighteen patients received RC48 alone, and 18 received RC48 combined with a programmed death-1 antibody. The median PFS was 5.4 months. The median OS was not reached. The 6-month and 1-year PFS rates were 38.8% and 15.5%, respectively. The 1-year OS rate was 79.6%. Fourteen (38.9%) patients achieved a partial response, and the ORR was 38.9%. Eleven patients had stable disease, and the DCR was 69.4%. The median PFS for patients who received RC48 combined with immunotherapy and those who received RC48 alone was 8.5 and 5.4 months, respectively. The main treatment-related adverse events included anemia, hypoesthesia, fatigue, and elevated transaminase. No treatment-related death occurred.ConclusionRC48 alone or combined with immunotherapy might benefit patients with locally advanced or metastatic UC, regardless of impaired renal function.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00262-023-03419-1.