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The current SARS-CoV-2 disease (COVID-19) pandemic is a sudden major stressor superimposed on pre-existing high distress in parents of infants admitted to the neonatal intensive care unit (NICU). This study aimed to investigate the psychological wellbeing of NICU parents during the COVID-19 pandemic. Forty-four parents of 25 inpatients of the Padua University Hospital NICU were included from June 2020 to February 2021. At 7–14 days postpartum parents completed the Edinburgh Postnatal Depression Scale (EPDS), State-Trait Anxiety Inventory (STAI), Parental Stressor Scale: NICU (PSS:NICU) and an ad-hoc questionnaire measuring parental COVID-19 related stress. About one third of parents reported extreme/high stress and a relevant negative impact on parenthood experience. Less time (82%) and less physical contact (73%) with infants due to COVID-19 preventive measures were the most frequent negative factors. Higher COVID-19 related parental stress was positively associated with anxiety, depression, NICU parental stress, stress related to NICU environment, and parental role alterations. Depression symptoms, stress related to infant condition and parental role alterations were higher in mothers. The pandemic affected parental emotional and relational wellbeing directly through additional stress due to COVID-19 concerns and indirectly through the impact of restrictions on the experience of becoming parents.