The aim of this prospective study was to examine the determinants of growth failure and the association with neurodevelopmental outcome in infants undergoing open-heart surgery. In 107 infants undergoing open-heart surgery for congenital heart disease (CHD), we evaluated weight at birth, at surgery, and at one year of age (expressed as z-scores). Neurodevelopmental status was assessed before surgery and at one year of age. Median age at surgery was 3.9 months (range: 0.1-10.2). Mean [+/-standard deviation (S.D.)] weight z-score at birth was -0.27 (+/-1.45), before surgery -1.34 (+/-1.45) (P<0.001 vs. birth weight), and at one year -0.86 (+/-1.35), (P<0.001 vs. weight at surgery). Poor preoperative weight (<10th percentile) was associated with genetic disorders [odds ratio (OR) 5.9, P<0.001], preoperative neurological abnormalities (OR 3.41, P<0.05), and older age at surgery (OR 1.01, P<0.05). Weight <10th percentile at one year was associated with the same factors as poor preoperative weight, however, also with risk adjustment for congenital heart surgery-1 (RACHS) score >3 (OR 3.22, P<0.05). Neurodevelopmental outcome at one year was not determined by growth failure. In conclusion, impaired body weight gain before surgery is followed by a catch-up growth after surgery. However, there is no relationship to neurodevelopmental outcome. Genetic comorbidity is the most significant factor for poor weight gain.