Background Parents’ stress resulting from hospitalization of their infant in the neonatal intensive care unit (NICU) produces emotional and behavioral responses. The National Institutes of Health–sponsored Patient Reported Outcomes Measurement Information System (PROMIS) offers a valid and efficient means of assessing parents’ responses. Objective To examine the relationship of stress to anxiety, depression, fatigue, and sleep disruption among parents of infants hospitalized in the NICU. Methods Thirty parents completed the Parental Stressor Scale (PSS:NICU) containing subscales for NICU Sights and Sounds, Infant Behavior and Appearance, and Parental Role Alteration, and the PROMIS anxiety, depression, fatigue, and sleep disturbance short-form instruments. Results PSS total score was significantly correlated with anxiety (r = 0.61), depression (r = 0.36), and sleep disturbance (r = 0.60). Scores for NICU Sights and Sounds were not significantly correlated with parents’ outcomes; however, scores for Alteration in Parenting Role were correlated with all 4 outcomes, and scores for Infant Appearance were correlated with all except fatigue. Conclusion Stress experienced by parents of NICU infants is associated with a concerning constellation of physical and emotional outcomes comprising anxiety, depression, fatigue, and sleep disruption.