This study aimed to compare the efficacy and safety of EUS-guided ethanol injection and 125I seed brachytherapy for malignant left-sided liver tumors which were difficult for trans-abdominal intervention. The study protocol was registered at Clinicaltrials.gov (NCT02816944). Twenty-six patients were consecutively and prospectively hospitalized for EUS-guided interventional treatment of refractory malignant left-sided liver tumors between June 2014 and June 2016. Liver masses were detected using EUS in 25 of 26 (96.2%) patients. EUS-guided interventional treatment was completed uneventfully in 23 of 26 (88.5%) patients using anhydrous ethanol injection (n = 10) or iodine-125 seed implantation (n = 13). Six months later, complete response was achieved in 15 of 23 (65.2%) patients and partial response in 8 of 23 (34.8%) patients. Patients with tumor residual have second-look EUS-guided interventional treatment (n = 5), radiotherapy (n = 2) or surgical resection (n = 1). Complete response was achieved after repeated interventional treatment in 3 of 5 patients who underwent second EUS-guided intervention; 2 patients required additional surgical resection but one succeed. No significant complications occurred. Therefore EUS-guided 125I seed brachytherapy is an effective and safe treatment modality for radical operation or promising palliative control of malignant left-sided liver tumors refractory to trans-abdominal intervention.