OBJECTIVE: To estimate the cost of establishing and operating a comprehensive syringe service program (SSP) free to clients in the United States. METHODS: We identified the major cost components of a comprehensive SSP: (one-time start-up cost, and annual costs associated with personnel, operations, and prevention/medical services) and estimated the anticipated total costs (2016 US dollars) based on program size (number of clients served each year) and geographic location of the service (rural, suburban, and urban). RESULTS: The estimated costs ranged from $0.4 million for a small rural SSP (serving 250 clients) to $1.9 million for a large urban SSP (serving 2,500 clients), of which 1.6% and 0.8% is the start-up cost of a small rural and large urban SSP, respectively. Cost per syringe distributed varied from $3 (small urban SSP) to $1 (large rural SSP), and cost per client per year varied from $2000 (small urban SSP) to $700 (large rural SSP). CONCLUSIONS: Estimates of the cost of SSPs in the United States vary by number of clients served and geographic location of service. Accurate costing can be useful for planning programs, developing policy, allocating funds for establishing and supporting SSPs, and providing data for economic evaluation of SSPs.