Needle-syringe programs (NSP) have been effective in reducing HIV and hepatitis C (HCV) infection among people who inject drugs (PWID). Achieving sustainable reductions in these blood-borne infections requires addressing structural factors so PWID can legally access NSP services. Systematic literature searches collected information on NSP coverage and changes in HIV or HCV infection prevalence or incidence at the population level. Included studies had to document biomarkers (HIV or HCV) coupled with structural-level NSP, defined by a minimum 50 % coverage of PWID and distribution of 10 or more needles/syringe per PWID per year. Fifteen studies reported structural-level NSP and changes in HIV or HCV infection prevalence/incidence. Nine reported decreases in HIV prevalence, six in HCV infection prevalence, and three reported decreases in HIV incidence. The results support NSP as a structural-level intervention to reduce population-level infection and implementation of NSP for prevention and treatment of HIV and HCV infection.