In a controlled study of the 499 available first degree relatives of 79 consecutive HLA-B27 positive patients with ankylosing spondylitis and 69 HLA-B27 positive healthy blood donors, 19 cases of ankylosing spondylitis were found: 16 (15 B27 positive) among the 282 relatives of the patients with ankylosing spondylitis, and 3 (1 B27 positive, 1 B27 negative, 1 unknown) among the 217 relatives of healthy donors ( , y : = 5.11; P < 0.025). However, if all cases of possible spondylarthritis are included, 48 cases of ankylosing spondylitis were found: 37 of 282 relatives of patients with ankylosing spondylitis and 11 of 217 relatives of healthy donors ( , y : = 8.29; P < 0.01). Assuming that 50% of relatives of B27 positive individuals carry this antigen, 15 of 142 (10.6%) B27 positive relatives of patients and 2 of 108 (1.9%) B27 positive relatives of healthy subjects ( , y : = 5.91; P < 0.025) have ankylosing spondylitis. The relative risk of spondylarthropathy for B27 positive relatives of B27 positive patients compared with relatives of B27 positive healthy subjects is 5.6. Assuming all subjects were evaluated in a similar manner, analysis of these data suggests genetic differences between B27 positive diseased individuals and B27 positive healthy subjects. Submitted for publication January 31, 1983; accepted in revised form July 22, 1983. In spite of the recognized association between ankylosing spondylitis (AS) and HLA-B27 (1,2), the precise nature of the predisposition to this disorder remains an enigma. About 20% of whites with HLA-B27 develop sacroiliitis (SI) (3-5) following an unknown inciting event. The figure reaches 50% for Pima Indian males (6). The environmental agent or agents that precipitate AS may be ubiquitous since the disease is prevalent with a worldwide distribution, the frequency of which mirrors that of B27 (7). It is also recognized that approximately 20% of subjects with HLA-B27 develop Reiter's syndrome (RS) after nonspecific urethritis (8), shigellosis (9), or other triggering events. The explanation of why the remaining 80% of people with HLA-B27 remain healthy is unclear. One possibility is that B27 positive patients with AS have an additional susceptibility gene or genes, that are lacking in healthy B27 positive subjects. Alternatively, B27 may not be homogeneic, that is, healthy B27 positive subjects may lack a hypothetical disease epitope present on B27 molecules of diseased individuals.To analyze these possibilities, studies can be performed both at epidemiologic and molecular levels. The former require in-depth family studies, whereas the latter rely on monoclonal antibody and biochemical investigations.We report a controlled study of the prevalence of AS among first degree relatives of B27 positive diseased individuals and among relatives of B27 positive healthy controls. A comparable prevalence of disease in both groups would provide evidence against genetic differences between the two B27 positive populations. Alternatively, if disease were found more frequen...