Many insurance payers in the US restrict access to direct-acting antivirals (DAA) for chronic hepatitis C (HCV) infection if patients have illicit substance use or are receiving opioid agonist treatment (OAT). Three phase 3 multi-center trials (the “ION” trials) evaluated the efficacy and safety of ledipasvir/sofosbuvir ± ribavirin in patients with chronic genotype 1 HCV infection. People receiving OAT were eligible, but those with drug use in the year prior to study initiation were excluded. Illicit drug use in the period following treatment initiation did not lead to discontinuation from these trials. In this post hoc analysis, researchers evaluated the impact of OAT (among patients enrolled in all phase 3 ION trials) and illicit drug use measured by serum toxicology testing on stored samples during therapy on: HCV treatment completion (among patients enrolled in the ION 1 trial only), adherence, sustained virologic response (negative HCV RNA viral load) 12 weeks post-treatment (SVR12), and safety of ledipasvir/sofosbuvir ± ribavirin.