Context The rate of tuberculosis (TB) among US homeless persons may be 20 times that of the general adult population. Studies suggest that the majority of urban homeless TB cases are attributable to ongoing transmission of TB. Optimal TB-control strategies in both chronically and transiently homeless populations are not known. Objective To examine the effects of TB-control strategies on projected TB cases and deaths in US homeless populations using a computer-based simulation model. Design, Setting, and Population The US general population and a theoretical population of 2 million homeless individuals in 1995 were divided into 18 clinical states based on the risk for or presence of TB and human immunodeficiency virus (HIV) infection in a semi-Markov model. Main Outcome Measures Prevalence of transiently and chronically homeless individuals with active TB and deaths from TB as a function of public health measures taken to control and eliminate TB, including improvement of treatment effectiveness, improvement in access to treatment, and vaccination with BCG. Results A 10% increase in access to treatment among homeless persons with active TB produced larger declines in predicted TB cases and deaths after 10 years (cases and deaths among chronically homeless persons decreased 12.5% and 19.8% and among transiently homeless persons dropped 35.9% and 32.4%, respectively) than improvements in the effectiveness of treatment programs (cases and deaths among chronically homeless persons declined 7.2% and 3.1% and among transiently homeless persons dropped 10.9% and 4.1%, respectively). A 10% increase in access to treatment among homeless persons with latent TB infection led to a 6.7% decline in TB among chronically homeless persons and a 5.7% decline among transiently homeless persons, while a 10% improvement in effectiveness of treatment for latent TB infection was associated with declines of 3.0% and 3.3%, respectively. When treatment for latent TB infection was modeled to be the same in vaccinated and nonvaccinated populations, BCG vaccination led to TB case declines of 15.4% and 21.5% in chronically and transiently homeless populations, respectively. Conclusions Overcoming barriers faced by homeless individuals in accessing TB treatment programs will be crucial to reducing the burden of TB in this high-risk group. Increased treatment access, improvement in the effectiveness of treatment programs, and BCG vaccination of HIV-negative homeless individuals have the best chance to markedly decrease TB morbidity and mortality.