The outcome of antidepressant therapy in terms of social functioning was evaluated in a randomized, placebo-controlled, double-blind study comparing the selective noradrenaline reuptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Of the 381 patients with major depression participating in the study, 302 patients were assessed using the new self-rating Social Adaptation Self-evaluation Scale (SASS). Mean SASS total score at last assessment was superior (p < 0.05) to placebo for both reboxetine and fluoxetine. Moreover, reboxetine was superior (p < 0.05) to fluoxetine. Evaluation of the sensitivity to change in individual items by point-biserial correlation analysis showed a significant correlation between improvement in item score and reboxetine treatment in all but one item for the reboxetine-placebo comparison. In the fluoxetine-placebo comparison, a significant correlation was evident for only 12 of the 21 items. Direct comparison of reboxetine with fluoxetine revealed a significant correlation between change in item score and treatment for nine items, in favour of reboxetine. The association was maximal for six items, mainly related to negative self-perception and to active social behaviour. In the subset of patients in remission at last assessment (n = 91), the mean SASS total score for reboxetine was superior to that of both fluoxetine and placebo (p < 0.05). Point-biserial correlation analysis revealed that most items sensitive to change under active treatment in the total population did so with reboxetine (17 items) or fluoxetine (nine items) in patients in remission. In the reboxetine-fluoxetine comparison, 14 items showed a significant association with reboxetine treatment. In conclusion, while social motivation and behaviour in depression are significantly affected by both noradrenergic and serotonergic antidepressant treatment, noradrenergic therapy seems particularly effective in improving negative self-perception and motivation towards action, resulting in a better quality of remission in terms of social functioning.