Objective: To test the hypothesis that remote ischemic conditioning (RIC) is safe and feasible as an adjunctive neuroprotective treatment in neonates with hypoxic-ischemic encephalopathy (HIE) during therapeutic hypothermia (TH). Study design: In this prospective, randomized, safety and dose escalation study in 32 neonates with HIE undergoing TH at a single quaternary referral NICU, four cohorts of consecutive patients received escalating therapy as follows: the first cohort of four patients received 3 minutes of limb ischemia by inflating a blood pressure cuff followed by 3 minutes of reperfusion; the second cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion; the third cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1 and 2 of TH; and the last cohort of four patients received 5 minutes of limb ischemia followed by 5 minutes of reperfusion on days 1, 2, and 3 of TH. For patients randomized to the control arm (n=16), a blood pressure cuff was applied without inflation. Each patient received 4 cycles of RIC or sham. Clinical, biochemical, and safety outcomes were monitored in both groups. Results: All patients received the designated RIC therapy without interruption or delay on days 1-3 of TH. RIC was not associated with increased pain, vascular, cutaneous, muscular, or neural safety events. There was no difference in the incidence of seizures, brain injury, or mortality between the two groups with the escalation of RIC dose and frequency. Conclusion: RIC is a safe and feasible adjunctive therapy for neonates with HIE undergoing TH. Future studies to investigate the potential efficacy of RIC for HIE are warranted.