The purpose of this study was to assess the stress among parents (either the mother or the father) of infants with neural tube defects (NTDs) and its associated factors. Using Parenting Stress Index–Short Form (PSI-SF), 100 parents of infants with NTDs were compared with 100 parents as a normative group. The total mean score for parents of infants with NTDs was 104.0 (standard deviation (SD) = 22.9) compared with 84.3 (SD = 18.9) for parents of infants without NTDs. Fifty-three (53.5%) parents of infants with NTDs and 15% of the control group had clinically significant high total stress score. Parents of infants with NTDs had a significantly higher score of distress in all scales of PSI-SF compared with those of infants without NTDs. Multivariate analysis found that mothers of infants with NTDs had a significantly higher average score for parental distress, parent–child dysfunctional interaction and total stress than fathers. Parents' lower education, unemployed parents and lower family income per month were significantly associated with increased parent–child dysfunctional interaction and parental distress. Parents with lower education and lower family income are in need for psychological and emotional support from health-care professionals.