METHODS Studies showing significantly higher concordance of tuberculosis among monozygotic twins than dizygotic twins have provided support for genetically determined susceptibility to tuberculosis. OBJECTIVE We wished to explore whether the development of delayed type hypersensitivity to tuberculin after newborn BCG immunization of twins suggested genetic regulation of the response to BCG in humans. METHODS Our study population consisted of 17 monozygotic twin pairs, 18 dizygotic twin pairs, and 64 single infants 3-34 months of age from Santiago, Chile. All had a BCG scar and were tuberculin tested by one trained nurse. RESULTS The mean birth weight of both groups of twins was significantly lower than that of singletons and the percentage of individuals who failed to respond to tuberculin was approximately twice as high in twins as in singletons. After adjustment for birth weight and age by regression analysis, it was found that the distribution of tuberculin reactivity in both monozygotic and dizygotic twins was not significantly different from that of singletons. Both twin pair correlations is adjusted tuberculin reactivity were significantly greater than zero (P < 0.01) and led to a heritability estimate of 0.28. However, the monozygotic twin correlation was not significantly larger than the dizygotic twin correlation so that heritability is poorly estimated. CONCLUSIONS These results are consistent with a genetic regulation of the response to newborn BCG immunization in humans by a mechanism capable of producing similar responses in identical and nonidentical twins alike.