Small volumes of hypertonic saline solution ([HS] 7.5% NaCl) produce systemic and microcirculatory benefits in hemorrhaged animals. Pentoxifylline (PTX) has beneficial effects when administrated after hemorrhagic shock. We tested the hypothesis that the combination of HS and PTX in the initial treatment of hemorrhagic shock provides synergistic hemodynamic benefits. Twenty-four dogs were bled to a target arterial blood pressure of 40 mm Hg and randomized into 3 groups: lactated Ringer’s solution (33 mL/kg; n = 6); HS (7.5% NaCl 4 mL/kg; n = 9); and HS+PTX (7.5% NaCl 4 mL/kg + PTX 15 mg/kg; n = 9). Systemic hemodynamics were measured by Swan-Ganz and arterial catheters. Gastric mucosal-arterial Pco2 gradient (Dg-aPco2; gas tonometry), portal vein blood flow (ultrasonic flowprobe), and systemic and regional O2-derived variables were also evaluated. HS induced a partial increase in mean arterial blood pressure, cardiac output, and portal vein blood flow. In the HS+PTX group, we observed a significant, but transitory, increase in systemic oxygen delivery (180 ± 17 versus 141 ± 13 mL/min) in comparison to HS alone. PTX infusion during hypertonic resuscitation promoted a significant reduction in Dg-aPco2 (41.8 ± 4.8 to 25.7 ± 3.9 mm Hg) when compared with isolated HS infusion (48.2 ± 6.4 to 39.4 ± 5.5 mm Hg). We conclude that PTX as an adjunct drug during hypertonic resuscitation improves cardiovascular performance and gastric mucosal oxygenation.