The stress experienced by parents at the time of diagnosis and hospitalization for their infant’s congenital heart defect (CHD) is well recognized by healthcare professionals. Increased parenting stress has been negatively correlated with development in low birthweight infants. The primary purpose of this study was to explore the parenting stress as experienced by parents of infants with CHD during their first six months of life. In addition, the relationship between parenting stress and the growth and development of infants with CHD was explored. Due to the transactional nature of mother-infant interaction, both directions of this relationship were examined, the factors of parenting stress predictive of growth and development and the factors of growth and development predictive of parenting stress. The change in stress over time was also evaluated. From a larger parent study examining feeding and energy balance in infants with CHD during their first year of life, 60 mother-infant dyads with complete data were selected. Thirty-five of these infants had a CHD (11 with single ventricle [SV] physiology) and 25 were healthy controls. Mothers completed infant temperament questionnaires and the Parenting Stress Index at 3 and 6 months, growth was also measured at these time points, and development was measured at 6 months utilizing the Bayley Scales of Infant Development-II. There were marked differences between subjects and controls; however, infants with SV physiology were found to bear an unequal share of adverse outcomes for infant temperament, parenting stress, and growth. Parenting stress correlated with and predicted growth and development. Growth and development however, did not predict parenting stress. It was predicted by temperament characteristics that comprise the “difficult” child constellation. Parenting stress decreased over time for all three groups. These original findings support the incorporation of parenting stress as a psychosocial variable in the exploration of biological phenomena such as infant growth and development. The importance of anticipatory guidance for parents of infants with SV physiology is stressed as well as the continued investigation of dyads to determine if the reported relationships in the first 6 months existed throughout the first year of life.