The treatment of chronic hepatitis C has been revolutionized with the introduction of direct-acting antivirals (DAAs). However, some patients are not cured with first-line treatment. Sofosbuvir/velpatasvir/voxilaprevir is a fixed-dose combination of a polymerase inhibitor, an NS5A inhibitor, and a protease inhibitor with activity against strains of the hepatitis C virus that show resistance to other first-line antiviral regimens. Sofosbuvir/velpatasvir/voxilaprevir has been studied in four Phase III randomized trials: POLARIS-1, −2, −3, and −4, which enrolled both treatment naïve and experienced patients with and without compensated cirrhosis. In these trials, at least 95% of patients treated with sofosbuvir/velpatasvir/voxilaprevir achieved sustained virological response (SVR). This includes favorable treatment outcomes in patients who had previously failed a regimen containing sofosbuvir or an NS5A inhibitor. Patient-reported outcomes also improved during and after treatment with sofosbuvir/velpatasvir/voxilaprevir. Treatment with sofosbuvir/velpatasvir/voxilaprevir is well tolerated, with the most commonly reported adverse events being headache, fatigue, diarrhea, and nausea. The approval of sofosbuvir/velpatasvir/voxilaprevir allows a treatment option for patients who have failed treatment with certain DAA regimens.