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Abstract Background Isolated persistent left superior vena cava (PLSVC) is a rare vascular anatomic variant, which can be an incidental finding at the time of an endovascular procedure. Case presentation This report describes the technical success, adverse events, and clinical outcomes of transjugular intrahepatic portosystemic shunt (TIPS) creation via isolated PLSVC. Three adult patients with cirrhosis and isolated PLSVC underwent TIPS placement successfully with one major adverse event. Two patients required TIPS revision within 90 days. There were no deaths within 90 days. Conclusions TIPS creation via isolated PLSVC is feasible using standard techniques with a left jugular vein approach. Caution is warranted during the procedure to assess for any aberrant drainage pattern to the left atrium and to prepare for potentially challenging instrument navigation through the coronary sinus.