Upon loading with parasite antigen and adoptive transfer, dendritic cells (DC) are able to confer protection against the protozoan parasite Leishmania major. In the present study, we investigated whether viable DC are required for inducing protection. We provide evidence that L. major antigen-loaded DC that had been fixed with paraformaldehyde or exposed to UV irradiation, and even disrupted cells, are able to serve as an effective vaccine. Furthermore, we demonstrate the potential of DC-derived exosomes to mediate protective immunity against cutaneous leishmaniasis. The route of antigen presentation to recipient T cells involves uptake of intravenously injected DC fragments into late endosomal compartments of splenic DC in the recipient. In vitro studies showed that DC fragments induce T-cell proliferation and interleukin 12 secretion by splenocytes. Together, these findings suggest that the development of a cell-free vaccine for immunoprophylaxis against leishmaniasis and other infectious diseases is feasible.