The American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) recommended in May 2019 that patients with hepatitis C virus (HCV) could be assessed for treatment initiation with a simplified treatment algorithm. This approach uses standard blood and fibrosis tests, rather than genotype testing, to guide the initiation of pan-genotypic direct-acting antiviral agents (DAAs) sofosbuvir/velpatasvir (SOF/VEL) or glecaprevir/pibrentasvir (GLE/PIB) treatment. To compare health care resource utilization (HCRU) and costs for patients who initiated treatment via the simplified vs nonsimplified algorithm (genotype testing). We identified adults with commercial and Medicare Advantage coverage who were diagnosed with HCV who initiated SOF/VEL or GLE/PIB from July 1, 2016, through August 31, 2019, in a nationally representative US administrative claims database. The index date was defined as the first pharmacy SOF/VEL or GLE/PIB fill date. Continuous enrollment 12 months before and ≥6 months after index date was required. Patients with claims for hepatitis B, HIV, decompensated liver, or prior DAAs were excluded. Patients were propensity score-matched (1:1) and grouped as “simplified” or “nonsimplified.” HCV-related HCRU and costs were compared for the post-matched groups. 3,539 HCV patients were included, and 16.6% initiated SOF/VEL or GLE/PIB via the simplified algorithm. Pre-matched treatments were SOF/VEL (52.8%) and GLE/PIB (47.2%). More than half (55.7%) of SOF/VEL and 44.3% of GLE/PIB patients started treatment via the simplified algorithm. HCV patients initiating via the simplified algorithm were more likely to be male (65.1% vs 60.6%; = 0.041), commercially insured (53.3% vs 46.5%; = 0.003), and in the Midwest (25.7% vs 19.3%; < 0.001) vs nonsimplified patients. The nonsimplified group had more liver disease (52.1% vs 46.9%; = 0.019), metabolic disorders (45.8% vs 39.2%; = 0.003), and dyslipidemia (39.9% vs 35.4%; = 0.041) vs the simplified group. Of the index prescriptions, 58.9% were written by gastroenterology or infectious disease specialists, and 68.1% (simplified) vs 75.4% (nonsimplified) had a specialist visit within 90 days prior to index DAA fill ( < 0.001). Matching resulted in 584 well-matched patients in each group. At post-match baseline, the simplified treatment group had significantly lower median (interquartile range [IQR]) HCV-related medical health care costs vs the matched nonsimplified group: $373 ($201-$684) vs $727 ($456-$1,185; < 0.001). Median noninpatient/emergency department health plan-paid costs were also significantly lower in the simplified cohort ($257 vs $504; < 0.001). During follow-up, medical HCV-related health care costs were similar across the groups. This study compared economic outcomes of HCV treatment initiation via the simplified and nonsimplified algorithms. The simplified approach resulted in lower use of health care resources, greater cost savings, and greater ability of patients to access care from both specialist and nonspecialist providers. While additional studies are needed, these early findings suggest a feasible path for simplified HCV treatment in real-world managed care settings. Funding support for this study was provided by Gilead Sciences, Inc. Majethia, Lee, Mozaffari, Wolf, and Hsiao are employees of Gilead Sciences, Inc. Bunner and Chastek are employees of Optum Life Sciences, which received funding from Gilead Sciences, Inc. to conduct this study. Bunner owns stock in UnitedHealth group, parent company of Optum. A poster based on selected data from this study was presented at the AMCP 2021 Virtual Meeting, April 12-16, 2021.