The study was undertaken to assess the potential effectiveness of combination HIV prevention on the very high seroprevalence epidemic among persons who inject drugs (PWID) in Tallinn, Estonia, a transitional country. Data from community-based cross-sectional (respondent driven sampling) surveys of PWID in 2005, 2007, 2009 and 2011 were used together with mathematical modeling of injection-associated HIV acquisition to estimate changes in injection-related HIV incidence during this period.Utilization of one, two or three of the interventions available in the community (needle/syringes exchange, antiretroviral treatment (ART), HIV testing, opioid substitution therapy) was reported by 42.5%, 30.5%, 11.5% of HIV+ and 34.7%, 36.4%, 5.7% of HIV- PWIDs, respectively in 2011. The modeling results suggest that the combination of needle/syringe programs and provision of ART to PWID in Tallinn substantially reduced the incidence of HIV infection in this population, from an estimated 20.7/100 person-years in 2005 to 7.5/100 person-years in 2011. In conclusion, combination prevention targeting HIV acquisition and transmission-related risks among persons who inject drugs in Tallinn has paralleled the downturn of the HIV epidemic in this population.