The tuberculin skin test (TST) using purified protein derivative (PPD) of Mycobacterium tuberculosis is traditionally used to diagnose latent tuberculosis (TB) infection (LTBI). However, LTBI diagnosis by peripheral blood mononuclear cell (PBMC) interferon (IFN)-γ responses to M. tuberculosis-specific antigens, early secreted antigenic target 6 kDa (ESAT-6) and culture filtrate protein (CFP)-10 has greater specificity. We investigated the difference in antimycobacterium cellular immunity in TB contacts who were strong TST reactors but nonresponsive to the ESAT-6/CFP-10 assay compared with those with concordant results. Healthy TB contacts were tested using the above two assays and mycobacterium survival was measured after co-culture of infected macrophages with their PBMCs. Whether PPD reactivity was tested by TST or by PBMC-specific IFN-γ responses, strongly PPD-reactive TB contacts without ESAT-6/CFP-10 responsiveness showed significantly better mycobacterium inhibition activity than ESAT-6/CFP-10-responsive TB contacts with the same PPD reactivity. In the former group, stronger PPD reactivity was associated with improved mycobacterium killing, whereas ESAT-6/CFP-10 responders showed the opposite result. PPD-reactive ESAT-6/CFP-10-nonresponsive TB contacts in our population may have had protective immunity related to prior mycobacterium exposure. ESAT-6/CFP10-responsive TB contacts are more likely to have LTBI and, in this group, strong PPD reactivity may paradoxically be associated with poor mycobactericidal activity. Copyright©ERS 2010.