The hypothalamic-pituitary-adrenal (HPA) axis overactivity is thought to contribute to increased vulnerability to maternal stress. We hypothesize that functionally relevant polymorphic variants of the glucocorticoid (NR3C1) and mineralocorticoid (NR3C2) receptor genes mediating biological effects of cortisol, a major stress hormone, could also modulate the capacity to cope with pregnancy-related anxiety. Genomic DNA from the blood of 42 women with pregnancy-related anxiety and 42 age-matched women with normal pregnancy (5–6th months of gestation) were genotyped for markers rs6195 and rs10482605 of NR3C1 and two NR3C2 polymorphisms (rs5522 and rs2070951) using a Taqman allele discrimination assay. Serum total cortisol was measured using an ELISA technique. The allele Ser363 of rs6195 (the N363S polymorphism of NR3C1) was found to be associated with a higher risk of maternal stress (odds ratio (OR)=5.27; P=0.001). For NR3C2, the allele Val180 of rs5522 (I180V) also showed association with increased risk of neonatal stress (OR=1.97; P=0.038). Both predisposing gene variants were also associated with significantly elevated levels of cortisol in normally pregnant women and females with pregnancy-related anxiety. Our results suggest that pregnancy-related anxiety can be modulated by variants of NR3C1 and NR3C2 associated with increased basal cortisol levels. Thus, our findings provide evidence in support of the suggestion that elevated cortisol levels and HPA axis hyperactivity are implicated in pregnancy-related anxiety.