Background: Depressive behavior in animals is often associated with reduced levels of brain-derived neurotrophic factor (BDNF) and impaired neurogenesis in the hippocampus. Recent studies showed that T cells recognizing central nervous system (CNS)-specific antigens can regulate adult hippocampal neurogenesis and expression of BDNF. On the basis of these findings, we hypothesized that controlling CNS specific immune activity by immunization with a myelin-related peptide may have an antidepressant effect. Methods: We investigated the impact of immunization with a CNS related peptide, on the behavioral and cellular outcomes of chronic mild stress (CMS; an animal model for depression) in rats. Results: Immunization with a weak agonist of a myelin-derived peptide ameliorated depressive behavior such as anhedonia (measured by sucrose preference), induced by CMS in rats. The behavioral outcome was accompanied by restoration of hippocampal BDNF levels and neurogenesis. Conclusions: The results of this study introduce a novel approach of immunization with CNS-related antigens as a therapeutic means for fighting depression. Vaccination, as an antidepressant therapy, may invoke several molecular and cellular pathways that are known to be regulated by antidepressant drugs. Therefore, we suggest that immune-based therapies should be considered for treatment of depression.