Background Patients with unresectable, chemorefractory hepatic metastases from colorectal cancer have considerable mortality. The role of transarterial radioembolization (TARE) with yttrium 90 (90Y) microspheres is not defined because most reports are from a single center with limited patient numbers. Purpose To report outcomes in participants with colorectal cancer metastases treated with resin 90Y microspheres from a prospective multicenter observational registry. Materials and Methods This study treated enrolled adult participants with TARE using resin microspheres for liver-dominant metastatic colorectal cancer at 42 centers, with enrollment from July 2015 through August 2020. TARE was used as the first-, second-, or third-line therapy or beyond. Overall survival (OS), progression-free survival (PFS), and toxicity outcomes were assessed by line of therapy by using Kaplan-Meier analysis for OS and PFS and Common Terminology Criteria for Adverse Events, version 5, for toxicities. Results A total of 498 participants (median age, 60 years [IQR, 52-69 years]; 298 men [60%]) were treated. TARE was used in first-line therapy in 74 of 442 participants (17%), second-line therapy in 180 participants (41%), and third-line therapy or beyond in 188 participants (43%). The median OS of the entire cohort was 15.0 months (95% CI: 13.3, 16.9). The median OS by line of therapy was 13.9 months for first-line therapy, 17.4 months for second-line therapy, and 12.5 months for third-line therapy (χ2 = 9.7; P = .002). Whole-group PFS was 7.4 months (95% CI: 6.4, 9.5). The median PFS by line of therapy was 7.9 months for first-line therapy, 10.0 months for second-line therapy, and 5.9 months for third-line therapy (χ2 = 8.3; P = .004). TARE-attributable grade 3 or 4 hepatic toxicities were 8.4% for bilirubin (29 of 347 participants) and 3.7% for albumin (13 of 347). Grade 3 and higher toxicities were greater with third-line therapy for bilirubin (P = .01) and albumin (P = .008). Conclusion Median overall survival (OS) after transarterial radioembolization (TARE) with yttrium 90 microspheres for liver-dominant metastatic colorectal cancer was 15.0 months. The longest OS was achieved when TARE was part of second-line therapy. Grade 3 or greater hepatic function toxicity rates were less than 10%. Clinical trial registration no. NCT02685631 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.