Tuberculosis (TB) is a major problem in the United States, yet little is known about the efficacy of intervention studies focused on enhancing completion of TB prevention programs among PPD positive homeless men and women, many of whom are addicted to drugs and alcohol, at risk for active TB, hard to reach and difficult to treat. In this prospective two-group quasi-experimental design, we will evaluate the effectiveness of a theoretically-based preventive intervention program focused primarily on compliance with TB chemoprophylaxis treatment, and secondarily on HIV risk reduction, with 480 sheltered men and women in the high TB prevalence area of Skid Row in Los Angeles. Initially, screening for chemoprophylaxis eligibility will be conducted with 6424 sheltered homeless living in the Skid Row area with anticipated PPD testing on a sample of 2762. Subsequent to final approval for chemoprophylaxis, a sample of 600 PPD positive homeless will be randomized by shelter into one of two programs, a Nurse Case Managed Plus Incentive (NCMI) Program or a Control Program. Participants in the NCMI program will receive the intervention by trained research nurses and outreach workers at the TB Satellite Clinic weekly over eight weeks, along with biweekly Directly Observed (DOT) and incentives for six months. Control group participants will receive basic care which includes biweekly DOT visits at the TB Satellite Clinic, and incentives for six months. All participants will be assessed at baseline and six-month follow-up using a battery of psychosocial, behavioral, health and physical status measures. The Comprehensive Health Seeking and Coping Paradigm will serve as the theoretical underpinning for guiding the assessment and implementation of strategies related to health outcome in this study. The long term goals of the study are to design effective programs for sheltered homeless individuals that focus on decreasing the spread of TB directly via completion of TB preventive programs for PPD positive individuals and indirectly via reduction of risk for HIV.