Objective: The monoaminergic stabiliser (−)-OSU6162 has in previous studies shown promising effects on mental fatigue after stroke and traumatic brain injury. This study investigated the safety and effectiveness of (−)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Methods: A total of 62 patients were randomly assigned to placebo or (−)-OSU6162. Primary outcomes were assessment on the mental fatigue scale (MFS) and the clinical global impression of change (CGI-C) scale. Secondary outcomes were results on the FibroFatigue scale (FF), the Beck Depression Inventory (BDI), the pain visual analogue scale and neuropsychological tests. Assessments were performed at baseline, after 1 and 2 weeks of treatment and at follow-up after 6 weeks. Results: MFS and CGI-C showed significant improvements for both treatment groups after treatment but not at follow-up; a similar pattern was seen for FF and BDI. However, significant differences between groups could not be demonstrated. On the other hand, correlation analyses showed a significant correlation between (−)-OSU6162 concentration and change in MFS, FF, and BDI score within the concentration interval 0.1–0.7 µM. Exploratory subgroup analyses showed a larger treatment effect with (−)-OSU6162 in improving MFS and FF symptoms in patients on antidepressant therapy compared to those without antidepressant treatment. Conclusion: (−)-OSU6162 was found to be safe and well tolerated. When analysing the entire material (−)-OSU6162 was not found to differ significantly from placebo in alleviating fatigue in ME patients but was superior to placebo in counteracting fatigue in a subgroup of ME patients who received concomitant pharmacological treatment for depression.