BACKGROUND/AIMS: Even though cognitive behavioral therapy has become a relatively effective treatment for major depressive disorder and cognitive behavioral therapy-related changes of dysfunctional neural activations were shown in recent studies, remission rates still remain at an insufficient level. Therefore, the implementation of effective augmentation strategies is needed. In recent meta-analyses, exercise therapy (especially endurance exercise) was reported to be an effective intervention in major depressive disorder. Despite these findings, underlying mechanisms of the antidepressant effect of exercise especially in combination with cognitive behavioral therapy have rarely been studied to date and an investigation of its neural underpinnings is lacking. A better understanding of the psychological and neural mechanisms of exercise and cognitive behavioral therapy would be important for developing optimal treatment strategies in depression. The SPeED study (Sport/Exercise Therapy and Psychotherapy-evaluating treatment Effects in Depressive patients) is a randomized controlled trial to investigate underlying physiological, neurobiological, and psychological mechanisms of the augmentation of cognitive behavioral therapy with endurance exercise. It is investigated if a preceding endurance exercise program will enhance the effect of a subsequent cognitive behavioral therapy. METHODS: This study will include 105 patients diagnosed with a mild or moderate depressive episode according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed.). The participants are randomized into one of three groups: a high-intensive or a low-intensive endurance exercise group or a waiting list control group. After the exercise program/waiting period, all patients receive an outpatient cognitive behavioral therapy treatment according to a standardized therapy manual. At four measurement points, major depressive disorder symptoms (Beck Depression Inventory, Hamilton Rating Scale for Depression), (neuro)biological measures (neural activations during working memory, monetary incentive delay task, and emotion regulation, as well as cortisol levels and brain-derived neurotrophic factor), neuropsychological test performance, and questionnaires (psychological needs, self-efficacy, and quality of life) are assessed. RESULTS: In this article, we report the design of the SPeED study and refer to important methodological issues such as including both high- and low-intensity endurance exercise groups to allow the investigation of dose-response effects and physiological components of the therapy effects. CONCLUSION: The main aims of this research project are to study effects of endurance exercise and cognitive behavioral therapy on depressive symptoms and to investigate underlying physiological and neurobiological mechanisms of these effects. Results may provide important implications for the development of effective treatment strategies in major depressive disorder, specifically concerning the augmentation of cognitive behavioral therapy by endurance exercise.