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Background: Needle exchange programs are effective public health interventions that reduce blood-borne infections, including hepatitis C, and injection-related infections. We sought to assess the return on investment of existing Prison Needle Exchange Programs (PNEPs) in Canadian federal prisons and their expansion to all 43 institutions., Methods: We developed a stochastic compartmental model that estimated hepatitis C and injection-related infections under different PNEP scenarios in Canadian federal prisons. Scenarios projected for 2018-2030 were no PNEP, status quo (actual PNEP implementation 2018-2022, with coverage maintained to 2030), and PNEP scale-up (coverage among people who inject drugs in prison increasing over 2025-2030 to reach 50% by 2030). We calculated the benefit-cost ratio as benefits from health care savings, divided by PNEP costs., Results: By 2019, PNEPs were implemented in 9 of 43 federal prisons, with uptake reaching 10% of people who injected drugs in prison in 2022. Compared with no PNEP, this was estimated to cost Can$0.45 (uncertainty interval [UI] $0.32 to $0.98) million and avert 37 (UI 25 to 52) hepatitis C and 8 (UI -1 to 16) injection-related infections over 2018-2030, with a benefit-cost ratio of 1.9 (UI 0.56-3.0). Compared with the status quo, the PNEP scale-up scenario cost an additional $2.7 (UI $1.8 to $7.0) million and prevented 224 (UI 218 to 231) hepatitis C and 77 (UI 74 to 80) injection-related infections, with a benefit-cost ratio of 2.0 (UI 0.57 to 3.3)., Interpretation: Every dollar invested in the current PNEP or its expansion is estimated to save $2 in hepatitis C and injection-related infection treatment costs. This return on investment strongly supports ongoing maintenance and scale-up of the PNEP in Canada from an economic perspective., Competing Interests: Competing interests:: Nadine Kronfli reports receiving research funding from the Canadian Institutes of Health and HIV/AIDS Research Initiative (grant numbers 190374 and 185725); Dr. Kronfli is also supported by a career award from the Fonds de Recherche Québec — Santé (FRQ-S; Junior 2). Mark Stoové reports receiving a Viiv Healthcare Medical Education Grant. No other competing interests were declared., (© 2024 CMA Impact Inc. or its licensors.)