Objective To compare physiological regulation and the effect of maternal sensitive caregiving during feeding on physiological regulation in healthy infants and in infants with transposition of the great arteries. Design Descriptive, 2 groups, repeated measures. Setting Three children's hospitals in the Midwest. Participants A convenience sample of 15 infants with transposition of the great arteries matched with 16 healthy infants. Methods Measures of physiological regulation before, during, and after feeding and quality of maternal affect and behavior during feeding were collected postoperatively at 2 weeks and 2 months of age. Results At 2 weeks, infants with transposition of the great arteries demonstrated impaired physiological regulation with feedings when compared with healthy infants. Healthy infants of more sensitive mothers were more likely to demonstrate a physiologically adaptive response during feeding. Maternal effect on physiological regulation was not observed in infants with transposition of the great arteries. No differences between groups were found at 2 months. Conclusions For infants with transposition of the great arteries, effects of surgical recovery and limited contact with their mothers relative to healthy infants may have outweighed the supportive effect of maternal sensitivity during feeding in the early weeks of life. Further research is needed to identify ways of enhancing the regulatory effect of maternal behavior on infants with heart defects.