ABSTRACT: Fibrocytes are unique, fibroblast-like cells with diverse functions and the potential for immunomodulation, which prompted investigation of their previously unexplored role in sepsis. Specifically, the study goals were to determine if adoptive transfer of fibrocytes would affect outcome in sepsis and to define relevant immunopathologic changes associated with the outcomes. Initial in vitro studies demonstrated that naive T-cell proliferation was significantly increased in cocultures with tissue-derived fibrocytes as compared with culture either alone or with fibroblasts. In vivo, the adoptive transfer of fibrocytes at the time of cecal ligation and puncture significantly improved survival of mice compared with transfer of fibroblasts or saline. Septic mice had lower blood levels of interleukin 6 (IL-6) and markers of organ injury after fibrocyte transfer as well as a reduced bacterial burden. Locally, peritoneal lavage fluid yielded lower bacterial counts, lower IL-6, and reduced inflammatory cell counts when fibrocyte transfer was compared with saline. This was also accompanied by significant increases in splenic CD4+ and CD8+ T cells. In vitro stimulation of the splenic T cells demonstrated that, after cecal ligation and puncture and adoptive transfer, the percentages of both CD4+ and CD8+ T cells with intracellular interferon γ were increased, whereas those with IL-4 remained similar between the groups. Therefore, it appears the adoptive transfer of fibrocytes improves sepsis survival, lowers bacterial burden, and promotes the proliferation of splenic T cells with a TH1 phenotype. These results confirm the immunomodulatory effects of exogenous, tissue-derived fibrocytes in sepsis and suggest their potential in cell therapy.