This phase 2 clinical trial measures the 3-month response rate of selective internal radiotherapy combined with chemotherapy as well as toxic effects, overall and progression-free survival, and disease control rate for patients with unresectable intrahepatic cholangiocarcinoma. Is selective internal radiotherapy associated with improved response rate in patients with unresectable intrahepatic cholangiocarcinoma? In this phase 2 clinical trial that included 41 patients, selective internal radiotherapy combined with chemotherapy was associated with an increased response rate of 39%, and 22% of patients were downstaged to surgical intervention. Median progression-free survival was 14 months, and median overall survival was 22 months. The findings suggest that selective internal radiotherapy can be considered as a treatment option for the downstaging of patients with unresectable intrahepatic cholangiocarcinoma. Patients with unresectable intrahepatic cholangiocarcinoma (ICC) have a poor prognosis. Selective internal radiotherapy (SIRT) is a promising treatment option for hepatic tumors, but no prospective studies of combination SIRT with chemotherapy have been published to our knowledge. To determine the response rate after SIRT combined with chemotherapy in patients with unresectable ICC. This phase 2 clinical trial, the Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC) trial, included patients with unresectable ICC who have never received chemotherapy or intra-arterial therapy and were treated at 7 centers which had experience with SIRT between November 12, 2013, and June 21, 2016. Statistical analysis was performed from March 31, 2017, to June 17, 2019. Concomitant first-line chemotherapy with cisplatin, 25 mg/m 2 , and gemcitabine, 1000 mg/m 2 (gemcitabine reduced to 300 mg/m 2 for the cycles just before and after SIRT), on days 1 and 8 of a 21-day cycle for 8 cycles. Selective internal radiotherapy was administered during cycle 1 (1 hemiliver disease) or cycles 1 and 3 (disease involving both hemilivers) using glass Y 90 microspheres. Response rate at 3 months according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Secondary end points were toxic effects, progression-free survival, overall survival, disease control rate, and response rate according to Choi criteria. Of 41 patients included in the study, 26 (63%) were male, with a mean (SD) age of 64.0 (10.7) years. Response rate according to RECIST was 39% (90% CI, 26%-53%) at 3 months according to local review and was confirmed at 41% as best response by central review; disease control rate was 98%. According to Choi criteria, the response rate was 93%. After a median follow-up of 36 months (95% CI, 26-52 months), median progression-free survival was 14 months (95% CI, 8-17 months), with progression-free survival rates of 55% at 12 months and 30% at 24 months. Median overall survival was 22 months (95% CI, 14-52 months), with overall survival rates of 75% at 12 months and 45% at 24 months. Of 41 patients, 29 (71%) had grades 3 to 4 toxic effects; 9 patients (22%) could be downstaged to surgical intervention, with 8 (20%) achieving R0 (microscopic-free margins) surgical resection. After a median of 46 months (95% CI, 31 months to not reached) after surgery, median relapse-free survival was not reached among patients who underwent resection. Combination chemotherapy and SIRT had antitumor activity as first-line treatment of unresectable ICC, and a significant proportion of patients were downstaged to surgical intervention. A phase 3 trial is ongoing.