BACKGROUND:There is limited evidence of the impact of needle and syringe programmes (NSPs) and opioid substitution therapy (OST) on hepatitis C virus (HCV) incidence among people who inject drugs (PWID), nor have there been any economic evaluations. OBJECTIVE(S):To measure (1) the impact of NSP and OST, (2) changes in the extent of provision of both interventions, and (3) costs and cost-effectiveness of NSPs on HCV infection transmission. DESIGN:We conducted (1) a systematic review; (2) an analysis of existing data sets, including collating costs of NSPs; and (3) a dynamic deterministic model to estimate the impact of differing OST/NSP intervention coverage levels for reducing HCV infection prevalence, incidence and disease burden, and incremental cost-effectiveness ratios to measure the cost-effectiveness of current NSP provision versus no provision. SETTING:Cost-effectiveness analysis and impact modelling in three UK sites. The pooled analysis drew on data from the UK and Australia. The review was international. PARTICIPANTS:PWID. INTERVENTIONS:NSP coverage (proportion of injections covered by clean needles) and OST. OUTCOME:New cases of HCV infection. RESULTS:The review suggested that OST reduced the risk of HCV infection acquisition by 50% [rate ratio (RR) 0.50, 95% confidence interval (CI) 0.40 to 0.63]. Weaker evidence was found in areas of high (≥ 100%) NSP coverage (RR 0.77, 95% CI 0.38 to 1.54) internationally. There was moderate evidence for combined high coverage of NSPs and OST (RR 0.29, 95% CI 0.13 to 0.65). The pooled analysis showed that combined high coverage of NSPs and OST reduced the risk of HCV infection acquisition by 29–71% compared with those on minimal harm reduction (no OST, ≤ 100% NSP coverage). NSPs are likely to be cost-effective and are cost-saving in some settings. The impact modelling suggest that removing OST (current coverage 81%) and NSPs (coverage 54%) in one site would increase HCV infection incidence by 329% [95% credible interval (CrI) 110% to 953%] in 2031 and at least double (132% increase; 95% CrI 51% to 306%) the number of new infections over 15 years. Increasing NSP coverage to 80% has the largest impact in the site with the lowest current NSP coverage (35%), resulting in a 27% (95% CrI 7% to 43%) decrease in new infections and 41% (95% CrI 11% to 72%) decrease in incidence by 2031 compared with 2016. Addressing homelessness and reducing the harm associated with the injection of crack cocaine could avert approximately 60% of HCV infections over the next 15 years. LIMITATIONS:Findings are limited by the misclassification of NSP coverage and the simplified intervention definition that fails to capture the integrated services that address other social and health needs as part of this. CONCLUSIONS:There is moderate evidence of the effectiveness of OST and NSPs, especially in combination, on HCV infection acquisition risk. Policies to ensure that NSPs can be accessed alongside OST are needed. NSPs are cost-saving in some sites and cost-effective in others. NSPs and OST are likely to prevent considerable rates of HCV infection in the UK. Increasing NSP coverage will have most impact in settings with low coverage. Scaling up other interventions such as HCV infection treatment are needed to decrease epidemics to low levels in higher prevalence settings. FUTURE WORK:To understand the mechanisms through which NSPs and OST achieve their effect and the optimum contexts to support implementation. FUNDING:The National Institute for Health Research Public Health Research programme.