A role for HHV-6 has been proposed in several autoimmune disorders (ADs), including multiple sclerosis (MS), autoimmune connective tissue diseases, and Hashimoto's thyroiditis. There are several potential mechanisms by which HHV-6 might induce autoimmune responses. HHV-6 could trigger autoimmunity through lysis of infected cells by exposing high amounts of normally sequestered cell antigens. Another potential trigger is represented by molecular mimicry, with the synthesis of viral proteins that resemble cellular molecules as a mechanism of immune escape. The virus could also induce aberrant expression of histocompatibility molecules, thereby promoting the presentation of autoantigens. CD46-HHV-6 interaction is a new attractive mechanism that has been proposed: HHV-6 could participate in neuroinflammation in the context of MS by promoting inflammatory processes through CD46 binding. Although HHV-6 has the ability to trigger all of the above-mentioned mechanisms, more studies are required to fully elucidate the possible role of HHV-6 as a trigger of AD. © 2014 Elsevier B.V. All rights reserved.