Families of patients with gluten-sensitive enteropathy (GSE) were typed for HLA-A and -B antigens as well as for HLA-DW3 antigen(s) using appropriate typing alloantisera. In addition, patients and families were typed for GSE-associated B cell antigens using alloantisera obtained from mothers and wives of patients. The data obtained suggest that disease occurs within families when two conditions were fulfilled: (1) the family member is homozygous for the GSE-associated B cell antigens and (2) the family member also bears the HLA-DW3 antigen(s) or an antigen usually associated with DW3. In addition, with the family studies it was possible to show that the gene(s) controlling the DW3 antigen(s) and those controlling the GSE-associated B cell antigens are separate nonlinked genetic loci, a fact which leads to the conclusion that GSE has a genetic basis in at least two genes. It is speculated that the genes responsible for GSE code for surface proteins which are physically associated on lymphoid cell membranes and which form receptors important to the initiation of disease.