Tobacco product waste (TPW) is one of the most ubiquitous forms of litter, accumulating in large amounts on streets, highways, sidewalks, beaches, parks, and other public places, and flowing into storm water drains, waste treatment plants, and solid waste collection facilities. In this paper, we evaluate the direct and indirect costs associated with TPW in the 30 largest U.S. cities. We first developed a conceptual framework for the analysis of direct and indirect costs of TPW abatement. Next, we applied a simulation model to estimate the total costs of TPW in major U.S. cities. This model includes data on city population, smoking prevalence rates, and per capita litter mitigation costs. Total annual TPW-attributable mean costs for large US cities range from US$4.7 million to US$90 million per year. Costs are generally proportional to population size, but there are exceptions in cities that have lower smoking prevalence rates. The annual mean per capita TPW cost for the 30 cities was US$6.46, and the total TPW cost for all 30 cities combined was US$264.5 million per year. These estimates for the TPW-attributable cost are an important data point in understanding the negative economic externalities created by cigarette smoking and resultant TPW cleanup costs. This model provides a useful tool for states, cities, and other jurisdictions with which to evaluate a new economic cost outcome of smoking and to develop new laws and regulations to reduce this burden.