Background: We assessed the therapeutic effects of venlafaxine XR and paroxetine on mood and anxiety symptoms derived from the tripartite model of mood. We hypothesized that the two antidepressants would have largely similar effects on symptoms of negative affect because both agents influence serotonergic systems. However, based on evidence indicating linkages between catecholaminergic activity and the emotional dimension of positive affect, we hypothesized that the catecholaminergic effects of venlafaxine XR would yield particularly pronounced effects on symptoms of positive affect. Methods: Twenty depressed outpatients were randomly assigned to treatment with either venlafaxine XR (225 mg/day) or paroxetine (30 mg/day) during a 12-week treatment trial. Weekly mood ratings were collected using the Mood and Anxiety Symptom Questionnaire [Watson, D., Clark, L.A., Weber, K., Assenheimer, J.S., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: II. Exploring the symptom structure of anxiety and depression in student, adult, and patient samples. J. Abnorm. Psychol. 104 (1), 15-25] [Watson, D., Weber, K., Assenheimer, J.S., Clark, L.A., Strauss, M.E., McCormick, R.A., 1995. Testing a tripartite model: I. Evaluating the convergent and discriminant validity of anxiety and depression symptom scales. J. Abnorm. Psychol. 104 (1), 3-14]. Results: Consistent with predictions, analyses revealed that there were no significant differences between venlafaxine XR and paroxetine on measures of negative affect. However, contrary to predictions, the two medications produced similar changes on measures of positive affect. Limitations: Replication and extension using a larger sample size are mandated. Conclusions: These preliminary results suggest that two antidepressants that appear to have dissimilar mechanisms of action may nevertheless have similar effects on the positive and negative affective components of depression. Alternatively, paroxetine may have a clinically relevant noradrenergic effect at the dose tested. © 2004 Elsevier B.V. All rights reserved.