Copyright © 2014 by Thieme Medical Publishers, Inc. Objective The objective of this study was to characterize the incidence, management, and short-term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating four separate prespecified definitions. Study Design Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP) < GA; (2) MAP < GA + signs of inadequate perfusion; (3) any therapy for CVI; or (4) inotropic therapy. Short-term outcomes included death, days on ventilation, oxygen, and to full feedings and discharge. Results Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes, and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotropic therapy was associated with increased mortality (11.1 vs. 1.3%; p < 0.05). Conclusion More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.