Newborn screening for cystic fibrosis (CF) is currently available through dried blood analysis for immunoreactive trypsinogen (IRT). The possible parenting stress associated with false-positive results or the early diagnosis of an asymptomatic infant has yet to be systematically addressed. This exploratory study examined levels of parenting stress among mothers of these infants. Results indicated significantly less total parenting stress but greater defensiveness in responding among families of false-positive screened children relative to their healthy comparison families. Parents of children diagnosed with CF through newborn screening did not show significantly higher stress scores than their healthy or "traditionally-diagnosed" CF comparison families. They did however have high frequencies of "at-risk scores" warranting referral based on clinical cut-off levels for Total Parenting Stress scores (45%) and Child Demandingness subscale score (50%). As the possibility for expanding CF neonatal screening to other states is considered, the need for further exploration of psychosocial sequelae affecting parenting will be increasingly important.