Results of a randomised controlled trial testing the EFFect Of Running Therapy on Depression. Background: This randomised controlled trial explored the anti-depressive and health effects of add-on exercise (running therapy or Nordic walking) in patients with Major Depressive Disorder (MDD). Methods: Patients were recruited at three specialised mental health care institutions. In the intervention group exercise was planned two times a week during 6 months, the control group received care as usual. Observer-blinded measurements included Hamilton-17 depression scores and several health and fitness parameters. Submaximal bicycle-tests were performed at inclusion, 3, 6 and 12 months. The effects of exercise were assessed by effect size, intention-to-treat and analysis per protocol using General Linear Models (GLM) with time x group interactions. Results: In total, 183 patients were assessed for eligibility and 135 were excluded (40% of the potential participants declined to participate mainly due to a lack of time and motivation). Together with a drop-out of 55% at 6 months, this reduced the power of the study severely. As a result, statistical analysis was performed only on the first 3 months of the study. Data were ultimately analysed from 46 patients, of which 24 were in the intervention group. Significantly more women were in the intervention group, and depression and fitness were higher in the control group. Participants showed 2-3 points less depression on average after 3 months. However, the GLM showed no effect on depression (Cohen's d < 0.2, F =.13, p =.73) in both the intention-to-treat and per protocol analyses. However, large effect sizes (Cohen's d > 0.8) were found for aerobic capacity (VO 2 max·.kg - 1, F = 7.1, p =.02∗), maximal external output (Wmax·.kg - 1, F = 6.1, p =.03∗), and Body Mass Index (F = 5, p =.04∗), in favour of the intervention group. Conclusions: In this selective and relative small clinical population with MDD, an anti-depressive effect of the exercise intervention could not be measured and is also unlikely due to the very low effect size. An integrated lifestyle intervention will probably be more effective than a single add-on exercise intervention. However, significantly increased fitness levels may contribute to the alleviation of current cardio-metabolic risk factors or prevention of these in the future. Trial registration: Netherlands Trial Register (NTR): NTR1894 on July 2nd 2009.