The objectives of this study were to investigate Tuberculosis (TB) knowledge, perceived risk, and risk behaviors in a sample of homeless persons with latent TB in the Skid Row district of Los Angeles. Particular emphasis was given to comparing these variables among homeless persons of varying ethnic backgrounds and among those who did and did not report a history of injection drug use (IDU). Baseline data were collected from 415 homeless individuals recruited to participate in a Tuberculosis chemoprophylaxis intervention. Areas of interest relative to TB knowledge and perceived risk for infection were behavioral factors surrounding substance use and abuse; personal factors measured in terms of current depression; and sociodemographic and situational factors, such as age, ethnicity, history of incarceration, and duration of homelessness. Findings revealed differences in substance abuse. IDUs were more likely to have histories of daily drug use and alcohol dependency, but were less apt to report recent use of crack cocaine. TB knowledge deficits centered on ignorance with respect to modes of transmission and risk factors for TB infection. IDU was also associated with depression. Latinos and IDUs were most likely to lack TB knowledge. There is a pressing need for accessible, available, culturally acceptable and sustained TB screening and intervention programs designed to address multiple risk factors and knowledge deficits with respect to TB infection in homeless populations.