['Susceptibility to spondyloarthritis (SpA) is largely genetically determined. To understand increasingly complex genetic associations, one approach is to study epistasis or genetic interactions. Several associations between HLA antigens and SpA including HLA-B27 have been reported. In this study, we investigated epistasis between common HLA class I risk antigens in ankylosing spondylitis (AS), the most typical form of SpA.', 'In 154 patients with AS and 5584 controls, HLA class I antigens were analysed for association with AS. Biological interaction was analysed by investigating whether the effects of the risk factors combined departed from additivity.', 'Apart from the association with HLA-B27, we found an association between HLA-B60 and AS (OR 1.8; 95% CI 1.2 to 2.8). This was confirmed in a meta-analysis (OR 2.2; CI 1.8 to 2.8). While 18.2% of AS patients had both HLA-B27 and HLA-B60, this combination was found in only 0.4% of controls. Using AS patients without HLA-B27 and HLA-B60 as a reference, the relative risk (RR) for disease in HLA-B27-/HLA-B60+ patients was 1.2 (95% CI 0.3 to 4.1). For HLA-B27+/HLA-B60- the RR was 69 (95% CI 40 to 111) but increased to 342 (95% CI 147 to 708) in HLA-B27+/HLA-B60+ patients. For the interaction, the relative excess risk due to interaction was 251, the attributable proportion was 0.8 and the synergy index was 4.7. The interaction was confirmed in an independent cohort.'] Does epistasis between two HLA antigens define a subset of individuals at a very high risk for ankylosing spondylitis?