Introduction: We developed a novel device, Calmer, that mimics key components of skin-to-skin holding to reduce stress in preterm infants. Our feasibility trial showed that Calmer worked 50% better than no treatment and no differently from our standard of care, facilitated tucking (FT), for reducing pain scores during a heel lance in preterm infants in the neonatal intensive care unit. Objective: We compared the effects of Calmer on regional cerebral hemodynamic activity during a noxious stimulation to FT. Methods: During a clinically required heel lance, we measured frontal cortex tissue oxygenation in a subsample of 29 preterm infants (27–33 weeks gestational age) from our larger randomized controlled trial. Infants were randomized to either FT (n 5 16) or Calmer treatment (n 5 12). The outcome measure, obtained using near-infrared spectroscopy, was a change in the tissue oxygenation index (TSI) across study phases (Baseline, Heel Lance, Recovery; median duration 517 seconds [421–906 seconds]). Results: No statistically significant differences were found between groups in the median TSI during any of the study phases. In response to the heel lance, 7 infants (27.6%) had a TSI that dipped below the 60% threshold (3 in the Calmer group 25% and 4 in the FT group 25%); none below 50%. Conclusions: Infants on Calmer maintained normal regional cerebral oxygen levels (55%–85%) no differently from infants receiving a human touch intervention during blood collection. Parental skin-to-skin holding is one of the most effective strategies to relieve procedural pain in preterm infants. When parents or FT are not available, Calmer shows potential for filling this gap in care.