AIM: To evaluate the cost-effectiveness of needle and syringe programmes (NSPs) compared with no NSPs on hepatitis C virus (HCV) transmission in the United Kingdom. DESIGN: Cost-effectiveness analysis from a National Health Service (NHS)/health-provider perspective, utilizing a dynamic transmission model of HCV infection and disease progression, calibrated using city-specific surveillance and survey data, and primary data collection on NSP costs. The effectiveness of NSPs preventing HCV acquisition was based on empirical evidence. SETTING AND PARTICIPANTS: UK settings with different chronic HCV prevalence among people who inject drugs (PWID): Dundee (26%), Walsall (18%) and Bristol (45%) INTERVENTIONS: Current NSP provision is compared with a counterfactual scenario where NSPs are removed for 10 years and then returned to existing levels with effects collected for 40 years. MEASUREMENTS: HCV infections and cost per quality-adjusted life year (QALY) gained through NSPs over 50 years. FINDINGS: Compared with a willingness-to-pay threshold of £20 000 per QALY gained, NSPs were highly cost-effective over a time-horizon of 50 years and decreased the number of HCV incident infections. The mean incremental cost-effectiveness ratio was cost-saving in Dundee and Bristol, and £596 per QALY gained in Walsall, with 78, 46 and 40% of simulations being cost-saving in each city, respectively, with differences driven by coverage of NSP and HCV prevalence (lowest in Walsall). More than 90% of simulations were cost-effective at the willingness-to-pay threshold. Results were robust to sensitivity analyses, including varying the time-horizon, HCV treatment cost and numbers of HCV treatments per year. CONCLUSIONS: Needle and syringe programmes are a highly effective low-cost intervention to reduce hepatitis C virus transmission, and in some settings they are cost-saving. Needle and syringe programmes are likely to remain cost-effective irrespective of changes in hepatitis C virus treatment cost and scale-up.