Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003‐2015). Patient data collected included the type of HE, medications, Model for End‐Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1‐4 months), and longer‐term (6‐12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty‐five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1‐4 and 6‐12 months, respectively. The majority (67%; 8/12) were free from HE‐related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. Liver Transplantation 22 723–731 2016 AASLD.