Hemorrhagic shock can be mitigated by timely and accurate resuscitation designed to restore adequate delivery of oxygen (DO2) by increasing cardiac output (CO). However, standard care of using systolic blood pressure (SBP) as a guide for resuscitation may be ineffective and can potentially be associated with increased morbidity. We have developed a novel vital sign called the compensatory reserve measurement (CRM) generated from analysis of arterial pulse waveform feature changes that has been validated in experimental and clinical models of hemorrhage. We tested the hypothesis that thresholds of DO2 could be accurately defined by CRM, a noninvasive clinical tool, while avoiding over-resuscitation during whole blood resuscitation following a 25% hemorrhage in nonhuman primates. To accomplish this, adult male baboons (n = 12) were exposed to a progressive controlled hemorrhage while sedated that resulted in an average (± SEM) maximal reduction of 508 ± 18 mL of their estimated circulating blood volume of 2,130 ± 60 mL based on body weight. CRM increased from 6 ± 0.01% at the end of hemorrhage to 70 ± 0.02% at the end of resuscitation. By linear regression, CRM values of 6% (end of hemorrhage), 30%, 60%, and 70% (end of resuscitation) corresponded to calculated DO2 values of 5.9 ± 0.34, 7.5 ± 0.87, 9.3 ± 0.76, and 11.6 ± 1.3 mL O2·kg·min during resuscitation. As such, return of CRM to ∼65% during resuscitation required only ∼400 mL to restore SBP to 128 ± 6 mmHg, whereas total blood volume replacement resulted in over-resuscitation as indicated by a SBP of 140 ± 7 mmHg compared with an average baseline value of 125 ± 5 mmHg. Consistent with our hypothesis, thresholds of calculated DO2 were associated with specific CRM values. A target resuscitation CRM value of ∼65% minimized the requirement for whole blood while avoiding over-resuscitation. Furthermore, 0% CRM provided a noninvasive metric for determining critical DO2 at approximately 5.3 mL O2·kg·min.