Aims/hypothesis Pathophysiological similarities between latent autoimmune diabetes in adults (LADA) and type 1 diabetes indicate an overlap in genetic susceptibility. HLA-DRB1 and HLA-DQB1 are major susceptibility genes for type 1 diabetes but studies of these genes in LADA have been limited. Our aim was to define patterns of HLA-encoded susceptibility/protection in a large, well characterised LADA cohort, and to establish association with disease and age at diagnosis. Materials and methods Patients with LADA (nâ€‰=â€‰387, including 211 patients from the UK Prospective Diabetes Study) and non-diabetic control subjects (nâ€‰=â€‰327) were of British/Irish European origin. The HLA-DRB1 and -DQB1 genes were genotyped by sequence-specific PCR. Results As in type 1 diabetes mellitus, DRB1*0301_DQB1*0201 (odds ratio [OR]â€‰=â€‰3.08, 95% CI 2.32â€“4.12, pâ€‰=â€‰1.2â€‰Ã—â€‰10âˆ’16) and DRB1*0401_DQB1*0302 (ORâ€‰=â€‰2.57, 95% CI 1.80â€“3.73, pâ€‰=â€‰4.5â€‰Ã—â€‰10âˆ’8) were the main susceptibility haplotypes in LADA, and DRB1*1501_DQB1*0602 was protective (ORâ€‰=â€‰0.21, 95% CI 0.13â€“0.34, pâ€‰=â€‰4.2â€‰Ã—â€‰10âˆ’13). Differential susceptibility was conferred by DR4 subtypes: DRB1*0401 was predisposing (ORâ€‰=â€‰1.79, 95% CI 1.35â€“2.38, pâ€‰=â€‰2.7â€‰Ã—â€‰10âˆ’5) whereas DRB1*0403 was protective (ORâ€‰=â€‰0.37, 95% CI 0.13â€“0.97, pâ€‰=â€‰0.033). The highest-risk genotypes were DRB1*0301/DRB1*0401 and DQB1*0201/DQB1*0302 (ORâ€‰=â€‰5.14, 95% CI 2.68â€“10.69, pâ€‰=â€‰1.3â€‰Ã—â€‰10âˆ’8; and ORâ€‰=â€‰6.88, 95% CI 3.54â€“14.68, pâ€‰=â€‰1.2â€‰Ã—â€‰10âˆ’11, respectively). These genotypes and those containing DRB1*0401 and DQB1*0302 associated with a younger age at diagnosis in LADA, whereas genotypes containing DRB1*1501 and DQB1*0602 associated with an older age at diagnosis. Conclusions/interpretation Patterns of susceptibility at the HLA-DRB1 and HLA-DQB1 loci in LADA are similar to those reported for type 1 diabetes, supporting the hypothesis that autoimmune diabetes occurring in adults is an age-related extension of the pathophysiological process presenting as childhood-onset type 1 diabetes. Electronic supplementary material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00125-006-0480-4 and is accessible to authorised users.