The A2 genes of Leishmania donovani encode amastigote-specific A2 proteins, which are considered to be virulence factors required for the survival of this protozoan parasite in the mammalian host. The A2 genes are present within a multigene family and corresponding A2 proteins are composed predominantly of multiple copies of a 10 amino acid repeat sequences. A2-specific antibodies have been detected in the sera of patients suffering from visceral leishmaniasis (VL) and it has been shown that generation of A2 deficient L. donovani resulted in an avirulent phenotype. In this report, we show that immunization of mice with recombinant A2 protein conferred significant protection against challenge infection with L. donovani. The protection correlated with in vitro splenocyte proliferation, production of IFN-gamma in response to A2 protein and the presence of A2-specific antibodies in the sera of immunized mice. These data demonstrate that A2 represents a potential antigen for protection against infection with L. donovani and VL.