EOP-JRA is an autoimmune disease that displays associations with DPB1*0201, DR8, DR5, and DR6, as well as an association with IL1A2 (a variant of IL1 alpha gene, not HLA linked). The purpose of this study was to analyze interactions between these genetic factors. We studied 103 EOP-JRA patients, 181 random controls, and 69 DR8-positive controls. We found a positive interaction between DPB1*0201 and the DRB1 alleles encoding DR3, DR5, or DR6, but not DR8. In addition, we found evidence for an interaction between IL1A2 and DR(3, 5, or 6) and DP2, but not DR8. We interpret the data to suggest heterogeneity in the HLA-associated pathogenic mechanisms of EOP-JRA.