Mothers of infants hospitalized in the Neonatal Intensive Care Unit (NICU) are at a high risk for psychological distress, which is of concern to health and social professionals due to the negative implications for mothers and infants. A model for explaining maternal psychological distress, consisting of intolerance to uncertainty and support from informal (spouse, family, and friends) and formal (medical staff) systems was examined. Data was collected from one of the largest NICUs in Israel; 129 mothers of 215 preterm infants completed self-report questionnaires regarding their background variables, intolerance to uncertainty, perceived informal support and perceived medical staff support. The NICU’s medical staff provided indicators for the infants of participating mothers. A hierarchical multiple regression analysis was conducted. The examined model explained 29.2% of the variance in maternal psychological distress. Intolerance of uncertainty positively predicted psychological distress. Informal support, and in particular, spousal support negatively predicted psychological distress above and beyond intolerance of uncertainty. Medical staff support negatively predicted psychological distress above and beyond intolerance to uncertainty and informal support. Our findings suggest that maternal psychological distress is reduced through a family-centered care approach in NICUs. Medical professionals and social services should develop further solutions for addressing preterm mothers’ need for certainty and support.