Background: When applied in the second-line treatment for biliary tract cancer (BTC) pts, surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) monotherapy has demonstrated moderate clinical efficacy and has demonstrated favorable tolerability and safety profiles. This study was to evaluate the efficacy and safety of surufatinib as a therapy for BTC in a real-world setting. In particular, pts who received resection for BTC with positive margins would be eligible for this study. This population indicates a poor prognosis, for their tumor environment is complex, which is an obstacle to R0 resection. However, no proper treatment for this population has been recommended yet. Methods: This is an ongoing single-arm, multi-center, open-label real-world study conducted in China. The study would enroll 200 pts with unresectable or surgical resection with positive margins BTC. Pts would receive surufatinib with or without combination as adjuvant (namely pts with positive margin after resection), first- or further-line therapy, at a proper dose (200-300mg) judged by physicians once per day in 28-day cycles. The primary endpoint is relapse-free survival (RFS) for pts whose primary lesions were resected, and progression-free survival (PFS) for those had evaluable lesions. If available, tumor assessments were performed every 2 cycles ± 7 days according to RECIST version 1.1. Results: By Sep 10, 2023, 56 eligible pts had been enrolled, of whom 16 (28.6%) were female. The median age was 64 (range: 39-81). 28 (50.0%), 24 (42.9%), and 4 (7.1%) pts received surufatinib as adjuvant, first-line, and above treatment, respectively. As to location, 23 cases were intrahepatic cholangiocarcinoma (ICC), and 33 cases were extrahepatic cholangiocarcinoma (ECC) or gallbladder cancer (GBC). With a median follow-up time of 9.5 (range: 1.1-20.3) mo, the global mRFS/mPFS was 10.4 (95% CI: 9.0-13.9) mo. The mRFS of pts who received surufatinib as adjuvant treatment was 11.3 (95% CI: 10.4-NA) mo, and mPFS of those who received surufatinib as systematic treatment was 9.0 (95% CI: 7.8-10.8) mo. Pts with ICC demonstrated an mRFS/mPFS of 10.4 (5.8-NA) mo, and those with ECC or GBC demonstrated 10.4 (9.5-NA) mo. The global mOS was 15.8 (12.4-NA) mo. Among those with primary lesion unresected (n=28), 2 pts (7.1%) achieved CR, 5 (17.9%) pts PR, 16 (57.1%) pts SD, and 5 (17.9%) pts suffered PD. The ORR was 25.0%, and DCR was 82.1%. No new safety signal was observed. Conclusions: Surufatinib exhibited promising efficacy and manageable toxicity on pts with BTC in the real-world setting. Clinical trial information: NCT05064852.