During MS, phagocytosing myelin-containing macrophages arise and lie in close proximity to T cells. To date, it has not been addressed whether these myelin-laden macrophages have the capacity to present antigens to T cells and whether this contributes to inflammation in disease. We demonstrate that in vitro-generated human and mouse myelin-laden macrophages expressed MHC class I and II and costimulatory molecules and are thus well equipped for antigen presentation. Human myelin-laden macrophages exhibited normal endocytosis of particulate and soluble antigens. In addition, human myelin-laden macrophages elicited active T cell proliferation of naïve as well as memory T cells. Furthermore, mouse myelin-laden macrophages induced primary antigen-specific CD4(+) T cell proliferation in vivo but transiently diminished IFN-γ release. Functionally, MOG peptide-loaded myelin-laden mouse macrophages modestly but significantly reduced the severity of MOG peptide-induced EAE. These data show that myelin uptake results in the induction of a population of macrophages that retains antigen-presenting capacity and limits autoimmune-mediated disease.