Endotoxemic shock is associated with approximately 50% incidence of acute kidney injury (AKI) and 70% mortality. Experimental studies indicate that endotoxemia-related AKI is associated with both hemodynamic and proinflammatory perturbations. We hypothesize that combined administration of albumin with pentoxifylline may protect against the development of AKI during endotoxemic shock in mice by maintaining the integrity of arterial circulation and exerting anti-inflammatory properties. We tested this hypothesis using an endotoxemic shock model produced by administering a high dose of lipopolysaccharide (LPS) (15 mg/kg intraperitoneal). LPS-treated mice developed hypotension compared to control mice (mean arterial pressure [MAP] 65.6 +/- 2.2 vs. 85.7 +/- 0.8 mm Hg, p < 0.05). Normal saline did not attenuate LPS-related hypotension (62.7 +/- 2.2 vs. 65.6 +/- 2.2 mm Hg, NS). Pentoxifylline, a phosphodiesterase inhibitor, worsened the LPS-related hypotension (50.7 +/- 6.9 vs. 65.6 +/- 2.2 mm Hg, p = 0.15) in a non-significant manner. Albumin alone caused a significant increase in MAP (79.3 +/- 4.7 vs. 62.7 +/- 2.2 mm Hg, p = 0.02), but had a non-significant modest effect on glomerular filtration rate (GFR; 60.8 +/- 24.7 vs. 38.2 +/- 18.2 microl/min, NS) compared to normal saline. However, the combination of albumin and pentoxifylline profoundly protected GFR (148.6 +/- 28.7 microl/min, vs. 38.2 +/- 18.2 microl/min, p < 0.01) as compared to normal saline. The combined administration of albumin and pentoxifylline significantly attenuated the renal iNOS protein expression and increased cardiac output. In summary, neither normal saline nor albumin nor pentoxifylline alone protected against endotoxemic shock-related AKI. However, the combination of albumin and pentoxifylline was effective in preventing AKI during endotoxemic shock. Thus, in endotoxemic shock, a multifactorial approach involving hemodynamic and anti-inflammatory effect may be necessary to decrease AKI.