•Cardiac surgery patients are at risk for post-traumatic stress disorder (PTSD) and depression, which might hamper recovery.•Factors associated with the development of PTSD and depression are variable.•Linear backwards regression identified higher trait anxiety to affect the occurrence of PTSD and depression significantly.•In this setting, female patients potentially benefit from intraoperative dexamethasone administration. Cardiac surgery patients are at risk for psychopathology. Symptoms of post-traumatic stress disorder (PTSD) and depression occur in 10–20% of these patients and affect their quality of life. The aim of this study was to assess factors associated with psychopathology after cardiac surgery. We followed participants of the multi-center randomized clinical trial Dexamethasone for Cardiac Surgery (DECS), on a single, intravenous dose of dexamethasone (1 mg/kg) or placebo during cardiac surgery, using validated questionnaires to assess PTSD and depressive symptoms after 1.5 to 4 years, as well as childhood trauma, trait anxiety, pre-existing psychopathology, and substance use. Saliva was used for genotyping of the hypothalamic-pituitary-adrenal-axis (HPA axis) glucocorticoid receptor gene. Linear backward regression analysis was performed with these factors, including pre-specified interaction terms of dexamethasone with sex and genotype. Complete data was available for 90% of cases (n = 1111). The model including trait anxiety and the dexamethasone x female sex interaction explained 57% of variance in PTSD symptoms (Model fit F (2;4.817)=643.043, p<.001; R2=0 0.57). Similar explained variance was seen for depressive symptoms, where age, trait anxiety and the dexamethasone x female sex interaction provided the optimal model (Model fit F (3;4.261)=435,960, p<.001; R2=0.58). In this study psychopathology was assessed through validated questionnaires. Variability in data collection detail was present. This study suggests that the occurrence of psychopathology after cardiac surgery is influenced by higher trait anxiety. Female cardiac surgery patients may benefit from intra-operative dexamethasone administration.