Background: The prognosis of advanced intrahepatic cholangiocarcinoma (ICC) remains dismal with gemcitabine-based first-line chemotherapy. This study is to evaluate the safety and efficacy of lenvatinib in combination with gemcitabine and oxaliplatin (Gemox) chemotherapy in the advanced ICC. Methods: Locally advanced or metastatic ICC patients (pts) were given lenvatinib 12 mg/day (body weight ≥60 kg) or 8 mg/day (body weight <60 kg) oral administration, once daily. They also received 1g/m² gemcitabine on Day 1 and Day 8, and 85 mg/m² oxaliplatin Q3W by IV for 6-8 cycles. The primary outcome was objective response rate (ORR) and secondary outcomes included safety, disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). ORR, DCR and PFS were measured according to RECIST 1.1. Treatment would be terminated by confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. Results: From March 2020 to Sep. 2020, 30 pathologically-confirmed advanced ICC pts with a mean age of 59.2 (range, 33-74) years, including 14 women (46.7%), were enrolled at Zhongshan Hospital, Fudan University. At the end of last follow-up (February 10, 2021), the ORR was 30.0% (9/30; 95% CI: 14.7%-49.4%). The disease control rate (DCR) was 86.7% (26/30; 95% CI: 69.3%-96.2%). Median follow-up was 6.8 months. One pt with locally advanced disease was down-staged and then underwent resection. This patient remained disease-free survival at the end of last follow-up. 11 pts experienced disease progression and 8 pts have died. The median PFS and OS have not been reached. Median duration of response (DOR) has not been reached and responses were ongoing in 6/9 (66.7%) pts. 6-months OS rate was 92.6%. No grade 5 adverse event (AE) was observed in present study. 40.0% (12/30) of pts experienced grade 3 or higher AEs and 5 pts discontinued the treatment owing to fatigue (3 pts), jaundice (1 pt) and vomiting (1 pt). Conclusions: Addition of lenvatinib to Gemox chemotherapy provided modest efficacy with reasonable tolerability in advanced ICC patients. Clinical trial information: (NCT04361331). Clinical trial information: NCT04361331