Background: Most new HIV infections among people who inject drugs (PWID) in eastern Europe and central Asia occur in Russia, where PWID have a high risk of overdose. In Russia, use of opioid agonist therapy (OAT) is prohibited, and coverage of needle and syringe programmes (NSPs) and antiretroviral therapy (ART) is poor. We aimed to assess the effects that scaling up harm reduction (ie, use of OAT and coverage of NSPs) and use of ART might have on HIV incidence and the frequency of fatal overdoses among PWID in two cities in the Ural Federal District and Siberian Federal District, where the prevalence of HIV is high or increasing in PWID. Methods: In this modelling study, we developed a dynamic deterministic model that simulated transmission of HIV through injection drug use and sex among PWID. We calibrated this model to HIV prevalence data among PWID in two Russian cities: Omsk (which has high but increasing prevalence of HIV among PWID) and Ekaterinburg (which has very high but stable prevalence of HIV). The source data were from research studies supported by the Global Fund to Fight AIDS, Tuberculosis, and Malaria and US Centers for Disease Control and Prevention and surveillance studies from WHO and regional AIDS centres. We modelled the effects of no intervention scale-up (no use of harm reduction measures and 30% of HIV-positive PWID receiving ART) versus combinations of scaling up of OAT, receipt of high coverage of NSPs, and use of ART on the incidence of HIV infections, mortality from HIV, and the frequency of fatal overdoses from 2018 to 2028. Findings: Without intervention, HIV prevalence among PWID in Omsk could increase from 30% in 2018 to 36% (2·5–97·5 percentile interval 22–52) in 2028 and remain high in Ekaterinburg, estimated at 60% (57–67) in 2028. Scaling up OAT to 50% coverage for a duration of 2 years could prevent 35% of HIV infections and 19% of deaths associated with HIV in Omsk and 20% (11–29) of HIV infections and 10% (4–14) of deaths associated with HIV in Ekaterinburg. Further, this scaling up could prevent 33% of overdose deaths over the next 10 years. Scaling up of NSPs and OAT to 50% coverage and tripling recruitment to ART (reaching about 65% of HIV-positive PWID) could prevent 58% (46–69) of HIV infections and 45% (36–54) of deaths associated with HIV in Omsk and 38% (26–50) of HIV infections and 32% (23–41) of deaths associated with HIV in Ekaterinburg by 2028. Interpretation: Legalisation of OAT and increased use of ART and NSPs for PWID are urgently needed to prevent HIV and fatal overdose among PWID in Russia. Funding: National Institutes of Health and Elton John AIDS Foundation.