Abstract Background Selective internal radiation therapy (SIRT) with yttrium-90 (⁹⁰Y) resin microspheres is an established locoregional treatment option for unresectable hepatocellular carcinoma (HCC), which delivers a lethal dose of radiation to hepatic tumors, while sparing surrounding healthy tissue. DOORwaY90 is a prospective, multicenter, open-label, single arm study, designed to evaluate the safety and effectiveness of ⁹⁰Y resin microspheres as first-line treatment in patients with unresectable/unablatable HCC. It is unique in that it is the first study with resin microspheres to utilize a personalized ⁹⁰Y dosimetry approach, and independent review for treatment planning and response assessment. Methods Eligibility criteria include unresectable/unablatable HCC, Barcelona Clinic Liver Cancer stage A, B1, B2, or C with a maximal single tumor diameter of ≤ 8 cm, and a sum of maximal tumor diameters of ≤ 12 cm, and at least one tumor ≥ 2 cm (long axis) per localized, modified Response Evaluation Criteria in Solid Tumors. Partition model dosimetry is used to determine the optimal dose; the target mean dose to tumor is ≥ 150 Gy. Patients are assessed at baseline and at regular intervals up until 12 months of treatment for response rates, safety, and quality of life (QoL). Post-treatment dosimetry is used to assess dose delivered to tumor and consider if retreatment is necessary. The co-primary endpoints are best objective response rate and duration of response. Secondary endpoints include grade ≥ 3 toxicity, QoL, and incidence of liver resection and transplantation post SIRT. Target recruitment is 100 patients. Discussion The results of this trial should provide further information on the potential use of SIRT with ⁹⁰Y resin microspheres as first-line therapy for unresectable HCC. Trial registration Clinicaltrials.gov; NCT04736121; date of 1st registration, January 27, 2021, https://clinicaltrials.gov/ct2/show/NCT04736121.