The present study was designed to evaluate the short-term safety, tolerability, and efficacy of a single intravenous administration of bone marrow-derived MSCs in a large-animal, peritonitis-induced sepsis model. The model was characterized by the development of the full spectrum of sepsis-induced organ dysfunction with typical hemodynamic, metabolic, and inflammatory host response phenotypes. The main findings indicate that: (1) the application of MSCs to healthy animals was well-tolerated without any measurable acute effects on macro- and microcirculatory hemodynamics, organ, and mitochondrial functions; (2) early treatment with MSCs failed to mitigate the development of sepsis-induced hemodynamic alterations including the progression of sepsis to septic shock; (3) MSCs did not confer any protection against alterations in cellular energy metabolism and multiple organ functions; and (4) treatment failed to counteract a gradual sepsis-driven systemic immune-inflammatory response.