The association between childhood celiac disease and the histocompatibility complex was studied in five multiply affected families and 20 unrelated patients. The diagnosis of celiac disease (CD) was established by three consecutive jejunal biopsies: 1) at the initiation of the diagnosis; 2) following a gluten-free diet; and 3) after gluten provocation. The results of this study indicate that a significant association exists between celiac disease, DR3 (P less than 0.001) and DR7 (P less than 0.001). The relative risks for these antigens were 8.56 and 5.05, respectively. Segregation analysis in the families suggested that the susceptibility genes associated with the histocompatibility antigens are not inherited in either a dominant or a recessive pattern. While an intermediate type fits better into the genetic framework of CD, more than one susceptibility and protecting gene may be involved in the pathogenesis of this disease.