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Summary Objectives We have previously reported that cognitive deficits are cross-sectionally associated with elevated cortisol in depressed patients. Here, we longitudinally examined if changes in cortisol secretion during treatment are associated with improvement of cognition. Methods Cognitive function and salivary cortisol levels were longitudinally examined in 52 patients with major depression before and after 3 weeks of standardized selective serotonin reuptake inhibitor (SSRI) and an add-on treatment modulating the mineralocorticoid receptor and compared to a healthy control group ( n = 50) matched for age, gender and years of education. Results Across add-on treatment groups, SSRI treatment reduced salivary cortisol in patients to levels of healthy controls (time × group interaction p = .05). In patients, reduction of cortisol significantly correlated with improvement in depressive symptoms ( r = .52, p < .01), speed of information processing ( r = .50, p < .01), and cognitive set-shifting ( r = .34, p = .03). Improved depressive symptoms were only associated with improved attention and working memory. Conclusions Improvement of some cognitive domains during SSRI treatment was associated with decreasing cortisol secretion and was only to a lesser extent associated with improved depressive symptoms.