The study aimed to evaluate the safety and effectiveness of selective internal radiation therapy (SIRT) in patients with unresectable hepatocellular carcinoma (HCC) in Vietnam. A single-arm, multicenter, prospective observational study on the use of SIRT in patients with HCC was conducted with 6 months of patient follow-up. At baseline, eligible patients had Eastern Cooperative Oncology Group (ECOG) status ≤1, total bilirubin ≤2 mg/dL, tumor burden ≤50%, Child-Pugh score A or ≤B7, and Barcelona Clinic Liver Cancer stage A – C. Patients with extrahepatic disease, signs of liver failure, or previous external beam radiation to the liver were excluded. Primary outcomes were tumor response according to modified Response Evaluation Criteria in Solid Tumors criteria, changes in liver function, and adverse events (AEs) assessed using Common Terminology for AEs v4.03 and the investigators’ clinical judgment. The secondary outcome was the percentage of patients alive at 6 months. Two centers enrolled 30 patients (median age 60 years) in 2017 and 2018. All patients were Child-Pugh A; among them, 28 were ECOG 0. Most had hepatitis B (n = 17, 57%) or D (n = 10, 33%). Target lesion response at 6 months was 23% complete response, 37% partial response, 7% stable disease, and 7% progressive disease. Of the 8 patients (27%) not evaluated, 2 had become eligible for resection, 2 had contraindications to imaging, and 4 were lost to follow-up. Laboratory values, including α-fetoprotein, did not change significantly from baseline to 6 months. The most common AEs were abdominal pain (37%) and vomiting (17%). Nine episodes of abdominal pain in 6 patients were treatment-related. Serious AEs included progressive cirrhosis (n = 1) and progression of HCC (n = 5). All patients were alive at 6 months. In conclusion, the safety and clinical effectiveness of SIRT were confirmed in patients with unresectable HCC in Vietnam.