The tuberculin skin test (TST) is used for the identification of latent tuberculosis (TB) infection (LTBI) but lacks specificity in Mycobacterium bovis BCG-vaccinated individuals, who constitute an increasing proportion of TB patients and their contacts from regions where TB is endemic. In previous studies, T-cell responses toESAT-6 and CFP-10, M. tuberculosis-specific antigens that are absent from BCG, were sensitive and specific for detection of active TB. We studied 44 close contacts of a patient with smear-positive pulmonary TB and compared the standard screening procedure for LTBI by TST or chest radiographs with T-cell responses to M. tuberculosis-specific and nonspecific antigens. Peripheral blood mononuclear cells were cocultured with ESAT-6, CFP-10, TB10.4 (each as recombinant antigen and as a mixture of overlapping synthetic peptides), M. tuberculosis sonicate, purified protein derivative (PPD), and short-term culture filtrate, using gamma interferon production as the response measure. LTBI screening was by TST in 36 participants and by chest radiographs in 8 persons. Nineteen contacts were categorized as TST negative, 12 were categorized as TST positive, and 5 had indeterminate TST results. Recombinant antigens and peptide mixtures gave similar results. Responses to TB10.4 were neither sensitive nor specific for LTBI. T-cell responses to ESAT-6 and CFP-10 were less sensitive for detection of LTBI than those to PPD (67 versus 100%) but considerably more specific (100 versus 72%). The specificity of the TST or in vitro responses to PPD will be even less when the proportion of BCG-vaccinated persons among TB contacts evaluated for LTBI increases.Tuberculosis (TB) remains a global public health problem with an estimated 3 million deaths and 8 million new cases yearly (14). In countries with a low incidence of TB, timely detection and treatment of latent TB infection (LTBI) in contacts of smear-positive pulmonary TB patients is required for containment of TB in the community, as latently infected persons are the main source of new TB cases (30). The tuberculin skin test (TST) has been used for detection of LTBI for almost a century. Interpretation of a TST result is often complicated in individuals vaccinated with Mycobacterium bovis bacillus Calmette-Guérin (BCG) or exposed to environmental mycobacteria due to the occurrence of cross-reactive (false-positive) immune responses to antigens present in tuberculin (protein purified derivative [PPD]) which are shared by those of nontuberculous mycobacteria and BCG (21, 27). In The Netherlands, skin testing is usually not performed in BCG-vaccinated persons, who are instead screened for LTBI by repeated chest radiographs (11). In the United States, in contrast, screening of BCG-vaccinated persons is by skin testing, and the criterion to define a positive test result is not different from that used in non-BCG-vaccinated persons (4). It has been proposed to base the interpretation of the TST in BCG-vaccinated persons on a number of individual and epidemiological p...