Aims To investigate whether opiate substitution therapy (OST) and needle and syringe programmes (NSP) can reduce hepatitis C virus (HCV) transmission among injecting drug users (IDUs). Design Meta-analysis and pooled analysis, with logistic regression allowing adjustment for gender, injecting duration, crack injecting and homelessness. Setting Six UK sites (Birmingham, Bristol, Glasgow, Leeds, London and Wales), community recruitment. Participants A total of 2986 IDUs surveyed during 2001-09. Measurement Questionnaire responses were used to define intervention categories for OST (on OST or not) and high NSP coverage (>= 100% versus <100% needles per injection). The primary outcome was new HCV infection, measured as antibody seroconversion at follow-up or HCV antibody-negative/RNA-positive result in cross-sectional surveys. Findings Preliminary meta-analysis showed little evidence of heterogeneity between the studies on the effects of OST (I-2 = 48%, P = 0.09) and NSP (I-2 = 0%, P = 0.75), allowing data pooling. The analysis of both interventions included 919 subjects with 40 new HCV infections. Both receiving OST and high NSP coverage were associated with a reduction in new HCV infection [adjusted odds ratios (AORs) = 0.41, 95% confidence interval (CI): 0.21-0.82 and 0.48, 95% CI: 0.25-0.93, respectively]. Full harm reduction (on OST plus high NSP coverage) reduced the odds of new HCV infection by nearly 80% (AOR = 0.21, 95% CI: 0.08-0.52). Full harm reduction was associated with a reduction in self-reported needle sharing by 48% (AOR 0.52, 95% CI: 0.32-0.83) and mean injecting frequency by 20.8 injections per month (95% CI: -27.3 to -14.4). Conclusions There is good evidence that uptake of opiate substitution therapy and high coverage of needle and syringe programmes can substantially reduce the risk of hepatitis C virus transmission among injecting drug users. Research is now required on whether the scaling-up of intervention exposure can reduce and limit hepatitis C virus prevalence in this population.