To demonstrate human leukocyte antigen (HLA)-linked control of susceptibility to pulmonary tuberculosis, 25 multiple-case families were tissue typed for class I and class II HLA specificities. Eight non-HLA genetic markers were also examined for any indication of other genetic factors that might influence the Mycobacterium tuberculosis infection. Observations on estimated HLA haplotype segregation in the sibs suggest that 84% of the affected sibs shared significantly more often than expected a common haplotype with each other than the normal unaffected sibs (P less than 0.001). Also, there was a skewed transmission of DR2 to diseased offspring from diseased parents (21 of 27) and to diseased offspring from healthy parents (15 of 17) in contrast to the transmission of DR2 from either group of parents to healthy offspring (six of 15 and 10 of 16, respectively). The segregation of non-HLA polymorphisms did not deviate significantly from the expected figures. These data provide strong evidence in favor of DR2-associated susceptibility to pulmonary tuberculosis.