CD11b+ Gr-1+-expressing cells, termed myeloid-derived suppressor cells, can mediate immunosuppression and tumor progression. However, the intrinsic molecular events that drive their protumorigenic behavior remain to be elucidated. Although CD11b+ Gr-1+ cells exist at low frequencies in normal mice, it also remains unresolved whether they are biologically distinct from those of tumor-bearing hosts. These objectives were investigated using CD11b+ Gr-1+ cells from both implantable (4T1) and autochthonous (mouse mammary tumor virus-polyomavirus middle T Ag (MMTV-PyMT)) mouse models of mammary carcinoma. Limited variation was observed in the expression of markers associated with immunoregulation between CD11b+ Gr-1+ cells of both tumor models, as well as with their respective controls (Cnt). Despite limited differences in phenotype, tumor-induced CD11b+ Gr-1+ cells were found to produce a more immunosuppressive cytokine profile than that observed by Cnt CD11b+ Gr-1+ cells. Furthermore, when admixed with tumor cells, CD11b+ Gr-1+ cells from tumor-bearing mice significantly enhanced neoplastic growth compared with counterpart cells from Cnt mice. However, the protumorigenic behavior of these tumor-induced CD11b+ Gr-1+ cells was significantly diminished when the expression of IFN regulatory factor 8, a key myeloid-associated transcription factor, was enhanced. The loss of this protumorigenic effect occurred independently of the host immune system and correlated with a CD11b+ Gr-1+ cytokine/chemokine production pattern that resembled cells from nontumor-bearing Cnt mice. Overall, our data indicate that 1) tumor-induced CD11b+ Gr-1+ cells from both cancer models were phenotypically similar, but biologically distinct from their nontumor-bearing counterparts and 2) modulation of IFN regulatory factor 8 levels in tumor-induced CD11b+ Gr-1+ cells can significantly abrogate their protumorigenic behavior, which may have important implications for cancer therapy.