To determine whether HLA-linked genes on chromosome 6 influence susceptibility to depressive disorders, we tested hypotheses concerning the distribution of HLA haplotypes among specific constellations of affected and unaffected family members. HLA haplotype identity among pairs of affected siblings in families with two affected siblings and among pairs of older unaffected siblings in families with one or two affected siblings was increased over random expectation (P less than 0.005). There was no increase in HLA haplotype identity among affected siblings in sibships with more than two affected members. When parents had a relative difference in estimated load of genes for susceptibility, HLA haplotypes were randomly transmitted to unaffected or affected children from the affected, "high-load" parent, but not from the unaffected, "low-load" parent (P less than 0.001). These results locate a gene contributing to susceptibility to depressive illness on chromosome 6 and provide a second example of the value of the hypotheses in defining the genetic bases of nonmendelian, familial diseases.