Following an initial negative Mantoux tuberculin skin test, a second test, given as soon as 1 wk later, has been shown to elicit markedly larger reactions (boosting) in 20 to 40% of refugees tested in the United States. We conducted a study to determine the explanation for this phenomenon. Using the Mantoux method of intradermal skin testing, 2,469 refugees from Southeast Asia were initially tested with tuberculin followed by sequential retesting 7 and/or 90 d later. They were also tested initially with nontuberculous mycobacterial antigens. A high proportion (35.5%) of Southeast Asian refugees had reactions (> or = 10 mm induration) to an initial tuberculin test, and 30.9% of the nonreactors exhibited boosting on a subsequent tuberculin test. Boosting, unlike reactivity to the initial tuberculin test, was not associated with exposure to a person with tuberculosis. However, boosting was associated with reactivity to nontuberculous mycobacterial antigens and a history of bacille Calmette-Guérin (BCG) vaccination. Boosting in this population is therefore attributable to environmental exposure to nontuberculous mycobacteria that are endemic in Southeast Asia or to BCG vaccination, rather than to remote infection with Mycobacterium tuberculosis. Sequential tuberculin screening and preventive therapy of persons with boosted reactions is not recommended as a tuberculosis prevention strategy in this population.