Infants admitted to the neonatal intensive care unit (NICU) often require surgical intervention and maintaining normothermia perioperatively is a major concern. In our preliminary study of 31 normothermic infants undergoing operative procedures in the operating room (OR), 58% (N = 18) returned hypothermic while all 5 undergoing procedures in the NICU remained normothermic (P = .001). To describe perioperative thermal instability (temperatures lower than 36.0°C) and frequency of associated adverse events, support interventions, and diagnostic tests in infants undergoing operative procedures in the OR and the NICU. This prospective, case-control study included 108 infants admitted to the NICU who were sequentially scheduled for an operative procedure in the OR (50.93%; N = 55) or the NICU (49.07%; N = 53). Existing data from the medical record were collected about temperatures and frequency of adverse cardiovascular, respiratory, and metabolic events, associated support interventions, and diagnostic tests during the perioperative period. Analyses examined the relative risks and proportional differences in rates of hypothermia between the OR group and the NICU group and associated adverse events, support interventions, and diagnostic tests between hypothermic and normothermic infants. Hypothermia developed in 40% (N = 43) of infants during the perioperative period. The OR group had a higher rate of perioperative hypothermia (65.45%, N = 36; P < .001) and were 7 times more likely to develop perioperative hypothermia (P = .008) than the NICU group (13.21%, N = 7). Likewise, infants in the OR group were 10 times more likely to develop hypothermia during the intra- and postoperative periods than those in the NICU group (P = .001). The hypothermic group had significantly more respiratory adverse events (P = .025), were 6 times more likely to require thermoregulatory interventions (P < .001), 5 times more likely to require cardiac support interventions (P < .006), and 3 times more likely to require respiratory interventions (P = .02) than normothermic infants. Although infants undergoing operative procedures in the OR experienced significantly higher rates of hypothermia than those undergoing procedures in the NICU, both groups experienced unacceptable rates of clinical hypothermia. Hypothermic infants experienced more adverse events and required more support interventions during the intra- and postoperative periods than normothermic infants, thereby demonstrating the negative sequelae associated with thermal instability. As a result, a translational team of key stakeholders has been created to explore multifaceted strategies based on translation science to implement, embed, and sustain perioperative thermoregulation best practices for the infant, regardless of the operative setting.