Our objective was to examine the cortisol release during a mental challenge in severe mental disorders versus healthy controls (HC), analyzing effects of sex, clinical characteristics and medication, and comparing Bipolar Disorder (BD) to Schizophrenia (SCZ). Patients with BD and SCZ (n=151) were recruited from a catchment area. HC (n=98) were randomly selected from the same area. Salivary samples were collected before and after a mental challenge and cortisol levels determined. During the challenge there was an interaction between group and sex (P = 0.015) with male patients having a blunted cortisol release compared to male HC (P = 0.037). Cortisol change did not differ significantly between BD and SCZ. In all patients, the cortisol change correlated with number of psychotic episodes (r = -0.23, P = 0.025), and in females patients, with number of depressive episodes (r = -0.33, P = 0.015). Patients using antidepressants had a greater cortisol release during challenge than those not using antidepressants (P = 0.043). Male patients with severe mental disorders seem to have a uniform abnormal cortisol release during mental challenges which associates with clinical course, and with beneficial effects of antidepressants.