BACKGROUND: The hepatitis C virus (HCV) prevalence rate among injection drug users (IDUs) in North America is 55.2%, with 1.41 million individuals estimated to be HCV-antibody positive. Studies have shown the effectiveness of syringe service programs (SSPs) alone, medications for opioid use disorder (MOUD) alone, or SSP+MOUD combination in reducing HCV transmission among opioid IDUs. OBJECTIVE: To evaluate the cost-effectiveness of SSP alone, MOUD alone, and SSP + MOUD combination in preventing HCV cases among opioid IDUs in the United States. METHODS: We used a decision tree analysis model based on published literature and publicly available data. Effectiveness was presented as the number of HCV cases avoided per 100 opioid IDUs. A micro-costing approach was undertaken and included both direct medical and nonmedical costs. Cost-effectiveness was assessed from a public payer perspective over a 1-year time horizon. It was expressed as an incremental cost-effectiveness ratio (ICER) and an incremental cost savings per HCV case avoided per 100 opioid IDUs compared with cost savings with "no intervention." Costs were standardized to 2019 U.S. dollars. RESULTS: The incremental cost savings per HCV case avoided per 100 opioid IDUs compared with no intervention were as follows: SSP + MOUD combination = $347,573; SSP alone = $363,821; MOUD alone = $317,428. The ICER for the combined strategy was $4,699 compared with the ICER for the SSP group. Sensitivity analysis showed that the results of the base-case cost-effectiveness analysis were sensitive to variations in the probabilities of injection-risk behavior for the SSP and SSP + MOUD combination groups, probability of no HCV with no intervention, and costs of MOUD and HCV antiviral medications. CONCLUSIONS: The SSP + MOUD combination and SSP alone strategies dominate MOUD alone and no intervention strategies. SSP had the largest incremental cost savings per HCV case avoided per 100 opioid IDUs compared with the no intervention strategy. Public payers adopting the SSP + MOUD combination harm-reduction strategy instead of SSP alone would have to pay an additional $4,699 to avoid an additional HCV case among opioid IDUs. Although these harm-reduction programs will provide benefits in a 1-year time frame, the largest benefit may become evident in the years ahead. DISCLOSURES: This research had no external funding. The authors declare no financial interests in this article. Ijioma is a Health Economics and Outcomes Research (HEOR) postdoctoral Fellow with Virginia Commonwealth University and Indivior. Indivior is a pharmaceutical manufacturer of opioid addiction treatment drugs but was not involved in the design, analysis, or write-up of the manuscript.