Purpose. Previous studies have shown single point HLA class II associations are risk factors for the development of idiopathic inflammatory myopathies (IIM). We have reported HLA class II differences between polymyositis (PM) and dermatomyositis (DM), (Arthritis Rheum 2002; 46: S397). The current study investigated the primary HLA class II associations in PM and DM, and which associations relate to PM/DM phenotype differences.Methods. DNA samples were obtained from 222 UK Caucasian patients with probable or definite (Bohan & Peter, 1975) myositis, comprising 116 PM and 106 DM. The presence of ILD and type of detectable circulating MSAs/MAAs were established. A randomly selected UK Caucasian control group (n=537) was used for genetic comparisons. Patients and controls were genotyped at HLA-DRB1, DQA1 and DQB1, using commercial kits.Results. HLA-DRB1*03, DQA1*05 and DQB1*02 were all risk factors for PM and DM. The primary independent risk factor in PM was HLA-DQA1*05 (Odds ratio [OR] 4.9, 95% confidence interval [CI] 2.7-8.8), whereas in DM it was HLA-DQB1*02 (OR 3.1, 1.8-5.3). These markers form part of the HLA-DRB1*03-DQA1*05-DQB1*02 haplotype, which is a significant risk factor for both PM/DM, but shows a differing association between the diseases (p=0.04). Patients with ILD, with or without anti-synthetase antibodies, also demonstrated strong associations with this haplotype, and irrespective of myositis subtype. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was a risk factor for the presence of anti-Mi-2 antibodies vs controls (OR 4.7, 95% CI 1.8-11.5), but a protective factor in PM vs controls (OR 0.4, 0.2-0.96). There was a difference in association between PM and DM (p=0.0002), which applied even in Mi-2 negative patients (p=0.002). Other MSA/MAAs also showed specific associations with other haplotypes, irrespective of myositis subtype.Conclusion. The results suggest that the HLA-DRB1*03-DQA1*05-DQB1*02 haplotype not only governs disease susceptibility in Caucasian PM/DM patients, but also some phenotypic features common to both disease subtypes. In contrast, even after allowing for the strong anti-Mi-2 antibody association, HLA-DRB1*07-DQA1*02-DQB1*02 discriminates between PM/DM disease susceptibilities. These differences support the notion that myositis patients with different myositis serology have different immunogenetic profiles, which may define specific myositis subtypes.