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Rationale: In his 1978 article on tuberculosis (TB) in twins, Comstock concluded that the 2.5-fold higher concordance rate for TB among monozygotic versus dizygotic twins in the Prophit survey of the 1950s implicated inherited susceptibility as a major risk factor for TB in humans. His analysis did not take into account strong imbalance of variables within subgroups, underestimating possible confounding effects of environmental factors. Objectives: To reconsider the role of environmental versus hereditary factors in determining the concordance rate of TB among twin pairs. Methods: Reanalysis of the Prophit Survey. Measurements and Main Results: A known Mycobacterium tuberculosis-positive or M. tuberculosis-negative sputum in the index TB case markedly influenced the odds ratio (OR) of concordance in the twin pairs. In 87 pairs with co-twins exposed to a sputum-negative index case, monozygotic and dizygotic twins did not differ in concordance for TB (OR, 1.1; 95% confidence interval [95% CI], 0.4-2.8). A higher concordance rate for TB among monozygotic versus dizygotic twins was confined to 106 pairs with the co-twins exposed to a sputum-positive index case (OR, 3.4; 95% CI, 1.6-7.2), and was highest in adolescent twins living together. ORs of TB concordance were proportional to intensity of exposure (sputum smear positivity, physical proximity between twin pairs, contagiousness of disease, and living together) rather than to zygosity. Conclusions: In the Prophit survey of susceptibility to TB among twins, environmental factors (i.e., intensity of exposure to tubercle bacilli) outweigh the importance of hereditary factors. Environmental factors and the context of transmission should be given more emphasis when studying interindividual and population differences in susceptibility to infectious diseases such as TB. [ABSTRACT FROM AUTHOR]