On May 2, 2005, a new in vitro test, QuantiFERON-TB Gold (QFT-G, Cellestis Limited, Carnegie, Victoria, Australia), received final approval from the U.S. Food and Drug Administration as an aid for diagnosing Mycobacterium tuberculosis infection. This test detects the release of interferon-gamma (IFN-g) in fresh heparinized whole blood from sensitized persons when it is incubated with mixtures of synthetic peptides representing two proteins present in M. tuberculosis: early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10). These antigens impart greater specificity than is possible with tests using purified protein derivative as the tuberculosis (TB) antigen. In direct comparisons, the sensitivity of QFT-G was statistically similar to that of the tuberculin skin test (TST) for detecting infection in persons with untreated culture-confirmed tuberculosis (TB). The performance of QFT-G in certain populations targeted by TB control programs in the United States for finding latent TB infection is under study. Its ability to predict who eventually will have TB disease has not been determined, and years of observational study of substantial populations would be needed to acquire this information. In July 2005, CDC convened a meeting of consultants and researchers with expertise in the field to review scientific evidence and clinical experience with QFT-G. On the basis of this review and discussion, CDC recommends that QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, evaluation of recent immigrants, and sequential-testing surveillance programs for infection control (e.g., those for health-care workers). This report provides specific cautions for interpreting negative QFT-G results in persons from selected populations. This report is aimed at public health officials, health-care providers, and laboratory workers with responsibility for TB control activities in the United States.