To investigate the clinical specificity of mixed affective states, we compared clinical characteristics of mixed (dysphoric) manics to those of agitated depressed patients. The subjects were inpatients studied in the NIMH Clinical Research Branch Collaborative Study on the Psychobiology of Depression, Biological Studies. Behavior and symptom ratings for depressive and manic symptoms were obtained during a 15-day placebo washout period. Patients with agitated depression were compared to those in acute manic episodes with and without prominent depressive symptoms. Mania ratings clearly distinguished agitated depressed from mixed manic patients. Concerning depression and general psychopathology, mixed manics had more severe agitation, hostility and cognitive impairment than did agitated depressed patients. Depressed mood and anxiety did not differ significantly between the two groups. Nurse ratings for depression and anxiety, based on ward behavior, were similar for mixed manics and agitated depressed patients, while physician-interview rated depression and anxiety were higher in agitated depressed patients. These data support the existence of superimposed depressive and manic syndromes in mixed manics.