The activity of catechol-O-methyltransferase (COMT) was determined in red blood cells of patients with primary affective disorder, schizophrenia, and antisocial personality, and in a control group. Reduction of COMT activity was noted in women with primary affective disorder. Activity of COMT paralleled the separation of women with primary affective disorder into two groups based on a past history of mania. Women with unipolar illness (depression only) had the lowest mean COMT activity whereas women with bipolar illness (depression with a history of mania or hypomania) demonstrated COMT activity intermediate between unipolar women and the control group. Red blood cell COMT activity was stable in patients and in control subjects up to eight months and the level of activity was not related to age, hospitalization, the presence of depressive symptomatology, or medication. These findings are discussed in relation to the catecholamine hypothesis of affective disorder. The validity of the unipolar-bipolar dichotomy in affective illeness is discussed.