Viral infections can be responsible for the onset and sustaining of autoimmune processes. We discuss how chronic inflammation associated with viral persistence is the prerequisite for initiation of a multi-step process leading to autoimmunity. Firstly, chronic inflammation may favor the priming of autoreactive T cells that have escaped thymic selection and are specific for self-mimicking viral peptides in the periphery. In addition, viral persistence and inflammation can act synergistically to induce and sustain autoimmunity either unveiling cryptic self-epitopes, or favoring determinant spreading, or activating dendritic cells, or promoting constant priming of new autoreactive T cells, or contributing to the efficient generation of effector cells, or, finally, restimulating memory T lymphocytes.