Background: Intrahepatic cholangiocarcinoma (ICC) is the second-most common primary liver malignancy. Immunotherapy plus chemotherapy regimen (such as TOP-AZ study) had demonstrated important therapeutic advantages in ICC, but the severe AEs reaction to chemotherapy might deteriorate treatment compliance, performance status and quality of life, and even subsequent treatment eligibility. Hence there is an unmet need for a more tolerable regimen with comparable efficacy for patients with unresectable ICC. The clinical benefits of combining Sintilimab and Anlotinib have been reported in a variety of clinical studies of solid tumors, such as non-small cell lung cancer and hepatocellular carcinoma. This trial aims to explore the safety and efficacy of Sintilimab plus Anlotinib in unresectable ICC. Methods: This is a prospective, single-arm, open-label exploratory, phase II study (ChiCTR2000035901). Eligible unresectable ICC patients received Sintilimab (200 mg, iv, d1) and Anlotinib (12 mg, po, d1-14) every 3 weeks till disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) assessed by RECIST v1.1 and secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall survival (OS), surgical conversion rate, as well as safety and tolerability. Results: Up to the end of January 2023, 18 patients were enrolled with a median age of 60.4 years (range 36-73), 61.1% were male, and all patients were classified into Child-Pugh A. 12 of 18 patients (66.7%) presented with TNM stage IV and 8 (8/18, 44.4%) patients had distant metastasis. All patients were efficacy evaluable, confirmed ORR was 33.3% and DCR was 83.3%. Of these, 16.7% (3/18) patients achieved complete response (CR), and 16.7% (3/18) patients achieved partial response (PR). Median PFS was 7.49 months (95% CI: 3.12-13.2). Among those, 3 (16.7%) patients further received surgical resection and 2 of 3 them were still disease-free survival till last follow-up. Treatment-related AEs (TRAEs) occurred in 12/18 pts (66.7%), while the most commonly reported TRAEs were hypertension in 29.6%. Grade 3 TRAEs occurred in 6/18 pts (33.3%) and there was no grade 4-5 TRAEs. Conclusions: In view of its encouraging efficacy and safety profile, Sintilimab plus Anlotinib might represents a viable and safe chemotherapy-free regimen in unresectable ICC treatment. Enrollment and further follow-up are ongoing. Clinical trial information: ChiCTR2000035901.