We reviewed reports of false-positive cultures for Mycobacterium tuberculosis and here propose guidelines for detecting and managing patients with possible false-positive cultures. Mechanisms of false-positive cultures included contamination of clinical devices, clerical errors, and laboratory cross-contamination. False-positive cultures were identified in 13 (93%) of the 14 studies that evaluated > or = 100 patients; the median false-positive rate was 3.1% (interquartile range, 2.2%-10.5%). Of the 236 patients with false-positive cultures reported in sufficient detail, 158 (67%) were treated, some of whom had toxicity from therapy, as well as unnecessary hospitalizations, tests, and contact investigations. Having a single positive culture was a sensitive but nonspecific criterion for detecting false-positive cultures. False-positive cultures for M. tuberculosis are not rare but are infrequently recognized by laboratory and clinical personnel. Laboratories and tuberculosis control programs should develop procedures to identify patients having only 1 positive culture. Such patients should be further evaluated for the possibility of a false-positive culture.