To examine the association between psychological distress and levels of salivary cortisol (SalC) and the ratio of serum cortisol to cortisol-binding globulin (SC/CBG) in pregnant women shortly after the diagnosis of a structural fetal anomaly. Design. A prospective, observational study. Setting. Tertiary referral center for fetal medicine. Population. Pregnant women with (study group, n=126) and without a fetal structural anomaly (comparison group, n=106) were included. Gestational age (GA) was >12weeks. Methods. Psychological distress was assessed by Impact of Event Scale (IES-22), General Health Questionnaire (GHQ-28) and Edinburgh Postnatal Depression Scale (EPDS). Salivary cortisol was measured in the evening and SC/CBG in the morning. Main Outcome Measures. Levels of SalC (in nanomoles per liter) and SC/CBG. Results. Median (range) GA at assessment was 19 (12–38) and 19 (13–22)weeks in the study and the comparison group, respectively. The study group had significantly higher psychological distress levels (p≤0.001) than the comparison group in all outcome measures. Salivary cortisol correlated with GA in both groups (p<0.004). In subanalyses including only women with GA 18–22weeks, and excluding smokers or women with chronic diseases or medication which might interfere with cortisol levels, there were no relations of SalC or SC/CBG with the psychometric variables in the study group. Conclusions. Women with detected fetal malformation had high psychological distress scores. The lack of association between psychological distress and SalC or SC/CBG suggests a blunted response of the hypothalamic–pituitary–adrenal axis following recent psychological stress activation in the second trimester of pregnancy.