Increasing evidence indicates that CD4CD25 T regulatory (Treg) cells control a wide spectrum of immune responses. The initial identification of CD4CD25 Treg cell as a "professional suppressor" was based on observations made in BALB/c mice. This mouse strain is well known to preferentially develop T helper cell type 2 responses, to be more susceptible to intracellular parasite infection, to have a higher tumor incidence, and to be more resistant to the induction of autoimmune diseases, as compared with C57BL/6 (B6) mice. We therefore decided to compare Treg cell function of B6 and BALB/c mice. We observed that the frequency of CD4CD25 T cells in the thymus and peripheral lymphoid organs of BALB/c mice was higher than in B6 mice. CD4 CD25 Treg cells from both mouse strains shared similar phenotypic properties, including expression of characteristic immunological markers and hyporesponsiveness to T cell receptor cross-linking and in their capacity to suppress proliferation of BALB/c CD4CD25 T responder (Tres) cells. However, CD4CD25 Tres cells from B6 mice were notably less susceptible to suppression by CD4 CD25 Treg cells from either mouse strain. Our data suggest that the number and the level of suppression of CD4CD25 Treg cells for CD4CD25 Tres cells may be dictated by genetic background. Our data also suggest that differences in the CD4CD25 Treg cell number and the susceptibility of CD4CD25 Tres cells may, at least in part, account for the differences in immune response between B6 and BALB/c strains of mice. © Society for Leukocyte Biology.