Background: Major liver resection remains associated with the potential for significant blood loss and transfusion. Numerous techniques are employed by surgeons and anesthesiologists to minimize this risk. Hypovolemic phlebotomy (HP) is one such technique that is novel and underreported. HP is not the same as acute normovolemic hemodilution. Observational data suggest that HP is highly effective at reducing blood loss and transfusion. Thus, the objective of this work was to carry out a feasibility randomized controlled trial (RCT) comparing HP to the standard of care, in order to inform a future multi-center trial. Methods: An RCT was carried out (June 2016-January 2018), comparing HP to the standard of care. HP consisted of the removal of 7–10 mL/kg of whole blood, without intravenous fluid replacement. Patients undergoing major liver resections or posterior sectionectomies were eligible. The main exclusion criteria were minor resections, hemoglobin <100 g/L, GFR <60 mL/min, and active cardiac conditions. Patients were randomized intraoperatively approximately 30 minutes prior to liver transection. The surgical team, nurses, and patient were blinded to the intervention using large drapes and scripted maneuvers by the anesthesiologist. The primary outcome was estimated blood loss (EBL). Feasibility was considered a co-primary outcome. Secondary outcomes included safety, morbidity and mortality, physiologic parameters, as well as transfusion. Results: A total of 62 patients were randomized to HP (n = 31) and control (n = 31). The two groups were evenly matched. The median EBL was 761 mL (451–1100) with HP and 872 mL (557–1248) with control (p = 0.458). Feasibility endpoints were met: 95% of eligible patients consented, 3.1 patients/month were randomized, surgeon blinding was maintained (98%), and HP was successfully applied (mean phlebotomy 607 ± 167 mL). Blinded surgeon perception questionnaires revealed that the ease of resection favored the HP group in 52% vs 32% (p = 0.0613), and that HP was correctly predicted in 65% of HP patients and incorrectly predicted in 32% of control patients (p = 0.0110, accuracy 66%). Overall complication rates were comparable (HP 32% vs control 48%, p = 0.196). There was no difference in major complications (HP 6.5% vs control 9.7%, p = 1.0) or in the median comprehensive complication index (p = 0.294). No difference was noted in the proportion of patients receiving a blood transfusion. Conclusion: This trial has successfully met its feasibility endpoints, but did not identify a significant difference in estimated blood loss. Safety endpoints were comparable between HP and the standard of care. The success of this trial justifies moving forward with a multi-center trial (PRICE-2) powered to identify a difference in perioperative blood transfusion rates.