Current recommendations conflict over the appropriate use of interferon-gamma whole blood assays to screen for tuberculosis (TB) infection in contact investigations. We report here on a worksite TB contact investigation in which tuberculin skin test (TST) and QuantiFERON-TB Gold (QFT-G) were both used to identify infection among 61 co-workers. Of the 27 (44%) who had a TST > or =15 mm, 11 (41%) had negative QFT-G, raising concerns that QFT-G may not be sufficiently sensitive when used alone in contact investigations. The questionable performance of QFT-G in this setting is not unexpected, as the negative predictive value of a test decreases with increasing prevalence.