Chronic hepatitis C virus (HCV) genotype 1 historically has been the most difficult to treat HCV genotype, and patients infected with this genotype had been previously treated with interferon-based therapy. In recent years, however, treatment options for chronic HCV infection have rapidly changed to an all-oral regimen. Ledipasvir–sofosbuvir is an oral fixed-dose (ledipasvir 90 mg–sofosbuvir 400 mg) combination of two direct-acting antiviral drugs. Four phase 3 clinical trials (ION-1–4) evaluated ledipasvir–sofosbuvir with and without ribavirin in patients with HCV genotype 1. High rates of sustained virologic response (SVR) occurred with ledipasvir–sofosbuvir alone in treatment-naïve and treatment-experienced patients without cirrhosis as well as in treatment-naïve patients with cirrhosis when administered for 12 weeks. In treatment-experienced patients with cirrhosis, 24 weeks of ledipasvir–sofosbuvir was also highly effective. Furthermore, treatment-naïve patients without cirrhosis (particularly those with HCV RNA serum concentrations < 6 million IU/ml) can achieve a similar SVR with only 8 weeks of therapy. Similarly, in patients coinfected with human immunodeficiency virus and HCV genotype 1 who were treated with ledipasvir–sofosbuvir for 12 weeks, a high SVR was observed in those with and without cirrhosis as well as treatment-naïve and treatment-experienced patients. Ledipasvir–sofosbuvir is well tolerated, with fatigue, headache, nausea, diarrhea, and insomnia being the most common adverse effects, which are typically mild to moderate in nature. This combination antiviral can be taken with or without food. Key factors to consider when prescribing ledipasvir–sofosbuvir are drug interactions including those mediated by the P-glycoprotein transporter and increased pH, cost of the drug or insurance coverage, comorbid conditions, and patient and provider preferences. Postmarketing experience and ongoing clinical trials will further define the safety and role of ledipasvir–sofosbuvir in the treatment of HCV genotype 1.