Objective The association of the human leucocyte antigen (HLA) system with thyroid carcinomas is not clear. We sought to relate HLA alleles to susceptibility to papillary thyroid carcinoma (PTC) and also to clinical and pathological characteristics of PTC patients. Design and patients The distribution of HLA in 181 unrelated Caucasian patients with PTC was compared to the HLA distribution in 315 normal controls, 31 patients with follicular carcinoma (FTC), 29 patients with lymphocytic thyroiditis (LT) and 50 patients with multinodular goitre (MNG), using a microlymphocytotoxicity assay. Results Compared to normal controls, patients with PTC showed a significantly increased frequency of HLA-DQ4 [12.8%vs. 3.5%, P = 0.0005, P-corrected (P-c) = 0.0032, odds ratio (OR) = 4.058, 95% confidence interval (95% CI) = 1.820-9.045] and HLA-DR8 (10.9%vs. 4.3%, P = 0.013, P-c > 0.05, OR = 2.752, 95% CI = 1.275-5.940). DQ4 and DR8 were also significantly increased in patients with MNG (DQ4, 16.3%; DR8, 16.3%) compared to controls (DQ4, P = 0.0019, P-c = 0.011, OR = 5.420, 95% CI = 1.978-14.852; DR8, P = 0.0044, P-c = 0.062). Linkage disequilibrium (LD) for these two alleles was present in controls (D = 0.0130, P = 9.7e-57) and in MNG patients (D = 0.0730, P = 4.6e-19) but not in PTC patients (D = 0.038, P > 0.05). In the subgroup of PTC subjects with concomitant nonthyroidal neoplasias (n = 27), there was a significant (P < 0.05) increase in the frequency of B57 (18.5%), DR11 (56.5%) and DQ3 (81.8%) compared to PTC patients without coexistent neoplasias (2.0%, 21% and 47%, respectively). No significant differences of HLA allele distribution was found in relation to PTC histology, age at diagnosis (> 45 or <= 45 years), gender or tumour-node-metastasis (TNM) staging. In patients with FTC, the frequency of DR17 (FTC = 51.6%; controls = 22.5%; P = 0.0009; P-c = 0.0138) was significantly increased compared to controls. Patients with LT showed a higher frequency of the DR11 allele (48.3%) than controls (DR11 = 21.3%; P = 0.0028, P-c = 0.039, OR = 3.445, 95% CI = 1.568-7.567). Conclusions We have typed the largest series of patients with thyroid carcinomas reported to date, and found that DR8 and DQ4 are independent susceptibility markers for PTC.