To examine whether increasing investment in needle/syringe exchange programs (NSPs) in the US would be cost-effective for HIV prevention, we modeled HIV incidence in hypothetical cases with higher NSP syringe supply than current levels, and estimated number of infections averted, cost per infection averted, treatment costs saved, and financial return on investment. We modified Pinkerton's model, which was an adaptation of Kaplan's simplified needle circulation theory model, to compare different syringe supply levels, account for syringes from non-NSP sources, and reflect reduction in syringe sharing and contamination. With an annual $10 to $50 million funding increase, 194-816 HIV infections would be averted (cost per infection averted $51,601-$61,302). Contrasted with HIV treatment cost savings alone, the rate of financial return on investment would be 7.58-6.38. Main and sensitivity analyses strongly suggest that it would be cost-saving for the US to invest in syringe exchange expansion.