The first two cases of indigenous variant Creutzfeldt-Jakob disease (vCJD) in the Republic of Ireland are reported in two men, neither of whom had lived outside Ireland. Both diagnoses were made ante-mortem based on clinical presentation, brain imaging, positive 14-3-3 protein in one case, and tonsillar biopsy. We discuss some of the clinical aspects of vCJD and the significance of these cases in the Irish context.