Persistent Hepatitis E Virus infection (HEV) is a rare but increasingly recognised condition in immunocompromised individuals. Untreated, this infection can rapidly progress to cirrhosis. Ribavirin is recommended as the first line treatment and the majority achieve sustained viral clearance. However, treatment options are limited for those who fail ribavirin. We report a case of a patients with ribavirin-refractory persistent HEV who responded to ledipasvir/sofosbuvir and ribavirin treatment. This patients had failed 2 course of ribavirin and 1 course of PEG-Interferon and ribavirin and he was known to harbour ribavirin-associated mutations (G1634R, D1384G and K1383N) in the RNA dependent RNA polymerase. He was treated with ledipasvir/sofosbuvir (LDV/SOF; Harvoni 90/400 mg) and ribavirin (R) 400 mg twice daily for 32 weeks. At treatment initiation his HEV RNA was 1.1 × 106 IU/ML and reduced to 1.8 × 104 IU/ML and 43 IU/ML at one and four weeks of treatment, respectively, becoming not detected in blood and stool by week eight. His blood HEV RNA remained undetectable for seven months after treatment completion. Unfortunately, at eight months post-treatment, his blood HEV RNA became detectable at a low level (35 IU/ML). His stool HEV RNA was also detectable at 620 IU/ML consistent with a late relapse. He restarted LDV/SOF+R and by week four of treatment HEV RNA was not detected in blood and stool. He remains on treatment. In conclusion, this is the first report demonstrating the antiviral activity of LDV/SOF+R in the treatment of persistent HEV infection.