We determined the cost of increasing access of injection drug users (IDUs) to sterile syringes and needles as an HIV prevention intervention in the United States and the cost per HIV infection averted by such a program. We considered a hypothetical cohort of 1 million active IDUs in the United States. Standard methods were used to estimate the cost and cost-effectiveness of policies to increase access to sterile syringes and syringe disposal at various levels of coverage (e.g., a 100% coverage level would ensure access to a sterile syringe for each injection given current levels of illicit drug injection in the United States; a 50% coverage level would ensure access to one half of the required syringes). A mathematical model of HIV transmission was employed to link programmatic coverage levels with estimates of numbers of HIV infections averted. A policy of funding syringe exchange programs, pharmacy sales, and syringe disposal to cover all illicit drug injections would cost just over $423 million U.S. for 1 year. One third of these costs would be paid for as out-of-pocket expenditures by IDUs purchasing syringes in pharmacies. Compared with the status quo, this policy would cost an estimated $34,278 U.S. per HIV infection averted, a figure well under the estimated lifetime costs of medical care for a person with HIV infection. At very high levels of coverage (>88%), the marginal cost-effectiveness of increased program coverage becomes less favorable. Although the total costs of funding large-scale IDU access to sterile syringes and disposal seem high, the economic benefits are substantial. Even at high levels of coverage, such funding would save society money. As part of a comprehensive program of HIV prevention, policies to increase IDUs access to sterile syringes urgently need further consideration by public health decision makers.