Our objectives were to estimate the annual number of injections by injection drug users (IDUs) in the United States of America, and to describe the potential role of pharmacists in providing IDUs with a sterile syringe for every injection. We estimated the number of annual injections by IDUs for the United States, selected U.S. states, and selected U.S. cities according to the following formula: number of injections per year = (number of IDUs) x (average number of injections per IDU per day) x 365. Data were obtained from published articles, personal communications with local experts, and selected national databases. We also reviewed published and unpublished studies of pharmacy kits, pharmacist attitudes, and pharmacist practices in the United States and abroad. Between 920 million and 1.7 billion injections by IDUs take place each year in the United States. We estimated 12 million injections per year in San Francisco and >80 million in New York City. A similar number of syringes would be needed to satisfy the goal of a sterile syringe for every injection. Pharmacy-based strategies, including the sale of kits for injection drug use, have provided sterile syringes to IDUs in Europe, Australia, and New Zealand. Modification of laws restricting syringe purchase and possession has led to marked increases in purchase of syringes from pharmacies and reductions in needle-sharing. In conclusion, large numbers of syringes would be required to provide a sterile syringe for every injection, but significant numbers of pharmacists seem to be willing to play a central role in syringe sale and distribution. Outreach programs should emphasize that using a sterile syringe for every injection is the optimal HIV prevention practice for IDUs who cannot or will not stop injecting. Pharmacy-based syringe sale or distribution has the potential to augment current efforts to prevent HIV infection in IDUs, their sex partners, and their children.