To avoid aggressive fluid resuscitation during hemorrhagic shock, fluid resuscitation is best guided by a specific measurement of tissue perfusion. We investigated whether fluid resuscitation guided by sublingual PCO2 would reduce the amount of resuscitation fluid without compromising the outcomes of hemorrhagic shock. Ten male domestic pigs weighing between 34 and 37 kg were used. Forty-five percent of estimated blood volume was removed during an interval of 1 h. The animals were then randomized to receive fluid resuscitation based on either sublingual PCO2 or blood pressure (BP). In the sublingual PCO2-guided group, resuscitation was initiated when sublingual PCO2 exceeded 70 Torr and stopped when it decreased to 50 Torr. In the BP-guided group, resuscitation was initiated when mean aortic pressure decreased to 60 mmHg and stopped when it increased to 90 mmHg. First, Ringer's lactate solution (RLS) of 30 mL kg was administered; subsequently, the shed blood was transfused if sublingual PCO2 remained greater than 50 Torr in the sublingual PCO2-guided group or mean aortic pressure was less than 90 mmHg in the BP-guided group. All the animals were monitored for 4 h and observed for an additional 68 h. In the sublingual PCO2-guided group, fluid resuscitation was required in only 40% of the animals. In addition, a significantly lower volume of RLS (170 ± 239 mL, P = 0.005 vs. BP-guided group) was administered without the need for blood infusion in this group. However, in the BP-guided group, all the animals required a significantly larger volume of fluid (955 ± 381 mL), including both RLS and blood. There were no differences in postresuscitation tissue microcirculation, myocardial and neurologic function, and 72-h survival between groups. During hemorrhagic shock, fluid resuscitation guided by sublingual PCO2 significantly reduced the amount of resuscitation fluid without compromising the outcomes of hemorrhagic shock.