Our objectives were to estimate the cost per syringe distributed for five syringe distribution strategies (a needle exchange program [NEP], a pharmacy-based NEP, free pharmacy distribution of pharmacy kits, sale of such pharmacy kits to injection drug users [IDUs], and sale of syringes in pharmacies); to assess the total costs of these strategies; and to conduct an economic analysis of these strategies in preventing HIV infection in IDUs. We estimated the costs for NEPs by using data from previous research; costs for the four pharmacy-based strategies were resource-based. Using estimates of the number of syringes required to provide a sterile syringe for each IDU injection, we estimated the total costs of the strategies in three representative U.S. cities. The lifetime cost of treating a person for HIV infection, discounted into current value, was used to estimate the number of syringes that could be distributed for that amount by the five strategies and thus the number of IDUs who could be ensured a sterile syringe for each injection. We then conducted a threshold analysis for calculating the annual HIV seroincidence for the program to be cost-neutral. The cost per syringe distributed in U.S. dollars was $0.97 for the NEP, $0.37 for the pharmacy-based NEP, $0.64 for pharmacy kit distribution, $0.43 for pharmacy kit sale, and $0.15 for syringe sale. The total annual cost in U.S. dollars of providing 50% of the syringes needed for a single syringe for every injection ranged from $6 to $40 million for New York City, from $1 to $6 million for San Francisco, and from $30,000 to $200,000 for Dayton, Ohio. The annual HIV seroincidence for the program to be cost-neutral compared with the cost of medical treatment for HIV injections was 2.1% for the NEP, 0.8% for the pharmacy NEP, 1.4% for pharmacy kit distribution, 0.9% for pharmacy kit sale, and 0.3% for syringe sale. All five strategies could distribute syringes at relatively low unit costs; NEPs would be the most expensive and syringe sales would be the cheapest. At annual seroincidences exceeding 2.1%, all strategies are likely to be cost-saving to society.