BACKGROUND: There is evidence that barriers exist for the initiation of direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) for those with substance use disorders (SUDs). However, real world clinical evidence of DAA treatment initiation following receipt of a prescription and continuation among those with SUDs and HCV is lacking. OBJECTIVES: To (1) compare HCV treatment initiation (prescription fill) rates and early discontinuation rates between HCV-infected patients with and without SUDs in the DAA era, and (2) identify patient-level factors associated with HCV treatment initiation and early discontinuation in patients with SUDs. METHODS: A retrospective cohort analysis of the MarketScan databases (January 2012-December 2018) was conducted for newly diagnosed treatment naïve HCV-infected patients (age ≥ 18) with and without SUDs. We used multivariable Cox regression to estimate adjusted hazard ratios (aHRs) with 95% confidence intervals of treatment initiation and early discontinuation in those with SUDs versus those without. RESULTS: We identified a total of 29,228 newly diagnosed HCV-infected patients (6,385 with SUDs and 22,843 without SUDs). Overall, DAA treatment initiation for patients with SUDs was significantly lower than that for those without SUDs (24% vs 34%; P < 0.01). After adjusting for demographics and clinical characteristics, patients with SUDs were less likely to initiate DAA treatments than those without SUDs (aHR, 0.87 [0.82-0.92]). There was no difference in discontinuation of DAA treatment between those with and without SUDs (4% vs 3%: aHR, 1.13 [0.81-1.60]). Among patients with SUDs (n = 6,385), lower rates of initiating DAA treatment was associated with younger age, and comorbidities including alcoholic liver disease (ALD; aHR, 0.44 [0.33-0.57), chronic kidney disease (CKD) (aHR, 0.52 [0.36-0.75]), and hepatitis B virus (HBV; aHR, 0.64 [0.44-0.92]). DAA treatment discontinuation was associated with younger age, ribavirin (RBV) therapy (aHR, 3.78 [2.21-6.47]), and cirrhosis diagnosis (aHR, 2.42 [1.21-4.84]) but not SUD treatment (aHR, 0.68 [0.34-1.34]). CONCLUSIONS: HCV-infected patients with SUDs had significantly lower treatment initiation rates, especially in young females and those with ALD, CKD, and HBV. No difference was found in DAA discontinuation. However, younger patients with RBV treatment and/or cirrhosis were more likely to stop treatment. Interventions directed towards these groups are needed to enhance DAA initiation and treatment maintenance among HCV-infected patients with SUDs. DISCLOSURES: Research reported in this publication was supported in part by the National Institute on Drug Abuse of the National Institutes of Health under award number K01DA045618 (to Park). The other authors have nothing to disclose that may present a potential conflict of interest.