OBJECTIVES Sofosbuvir (SOF) is a uridine analogue polymerase inhibitor. Ledipasvir (LDV) is an inhibitor of the hepatitis C virus (HCV) NS5A protein. Efficacy and safety have been demonstrated in three phase III clinical trials of LDV/SOF administered with or without ribavirin. This analysis evaluated the long-term outcomes of LDV/SOF in GT1 treatment-naïve (TN) and treatment-experienced protease inhibitor failure patients (TE) HCV patients. METHODS A Markov-model followed 10,000 patients for a lifetime, with 19% initiating treatment at the compensated cirrhotic (CC) stage. In GT1 TN, LDV/SOF for 8 weeks for non-cirrhotic (NC) patients and 12 weeks for CC patients was compared against SOF with pegylated interferon 2a and ribavirin (SOF/PR), SOF with RBV (SOF/RBV) and simeprevir with PR (SMV/PR). In GT1 TE, LDV/SOF for 12 weeks was compared with SOF/PR, SMV/PR and no treatment. SVR rates have been reported as 94% for GT1 TN NC and CC patients, 95% and 86% for GT1 TE NC and CC respectively. SOF/LDV was also well tolerated without any reported grade 3/4 adverse events. RESULTS SOF/LDV was shown to be highly effective in preventing advanced liver disease (ALD) and mortality due to HCV. In GT1 TN, LDV/SOF prevented more than 800, 200 and 1600 cases of ALD than SMV/PR, SOF/PR and SOF/RBV. In GT1 TE over 5000 cases of ALD were avoided compared with no treatment and over 1000 compared with SMV/PR, and SOF/PR. LDV/SOF was also shown to save more than 10 lives compared with SMV/PR, SOF/PR and SOF/RBV and avoid the death of 50 TE PI failure patients with no available treatment option. CONCLUSIONS LDV/SOF was shown to be highly effective in preventing progression to ALD and reducing HCV-related mortality with a well-tolerated single tablet regimen. This is particular important for protease inhibitor failure patients since there are currently no alternative treatment options.