Background. We evaluated the effectiveness and cost-effectiveness of interventions targeting hepatitis C virus (HCV) and HIV infections among people who inject drugs (PWID) in Eastern Europe/Central Asia. We specifically considered the needle-syringe program (NSP), opioid substitution therapy (OST), HCV and HIV diagnosis, antiretroviral therapy (ART), and/or new HCV treatment (direct acting antiviral [DAA]) in Belarus, Georgia, Kazakhstan, Republic of Moldova, and Tajikistan. Methods. We developed a deterministic dynamic compartmental model and evaluated the number of infections averted, costs, and incremental cost-effectiveness ratios (ICERs) of interventions. OST decreased frequencies of injecting by 85% and NSP needle sharing rates by 57%; ART was introduced at CD4 <350 and DAA at fibrosis stage .F2 at a 2370to23 280 cost. Results. Increasing NSP+OST had a high impact on transmissions (infections averted in PWID: 42% in Tajikistan to 55% in Republic of Moldova for HCV; 30% in Belarus to 61% in Kazakhstan for HIV over 20 years). Increasing NSP+OST+ART was very cost-effective in Georgia (ICER = 910/yearoflifesaved[YLS]),andwascost−savinginKazakhstanandRepublicofMoldova.NSP+OST+ARTand HIVdiagnosiswasverycost−effectiveinTajikistan(ICER=210/YLS). Increasing the coverage of all interventions was always the most effective strategy and was cost-effective in Belarus and Kazakhstan (ICER = 12960and21 850/YLS); it became cost-effective/cost-saving in all countries when we decreased DAA costs. Conclusion. Increasing NSP+OST coverage, in addition to ART and HIV diagnosis, had a high impact on both epidemics and was very cost-effective and even cost-saving. When HCV diagnosis was improved, increased DAA averted a high number of new infections if associated with NSP+OST.