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Objective It remains an unresolved research objective to clarify the overlap/association between fatigue (especially its cognitive facet) and depression in People with MS (PwMS). Therefore, in this study the patterns of personality and primary emotional traits (PETs) associated with each (motoric/cognitive fatigue and depression in PwMS) were investigated and compared in order to disentangle the three constructs in PwMS. Additionally, differences in personality and PETs between PwMS and healthy controls (HC) were examined. Method Associations between motoric/cognitive fatigue, depression, personality and PETs were investigated in 52 PwMS. Personality and PETs were also assessed in a gender matched HC sample (N = 52) and results regarding these were compared between PwMS and HC. Results Low extraversion was the only significant predictor of MS related motoric fatigue (β = -.341, p = .013). High neuroticism was a predictor of both MS related cognitive fatigue (β = .426, p = .002) and depression (β = .443, p < .001). Whereas neuroticism was the only significant predictor for MS related cognitive fatigue, the cluster of (high) neuroticism, (high) SADNESS (β = .273, p = .023), and (low) extraversion (β = -.237, p = .025) predicted MS related depression. PwMS showed significantly higher scores in neuroticism and FEAR compared to HC. Conclusions MS related motoric/cognitive fatigue and depression in PwMS share variance. But the substantial amount of non-shared variance (motoric fatigue, depression: 72%; cognitive fatigue, depression: 66%) together with additional predictors for depression (SADNESS being a predictor of depression only), indicate that MS related motoric/cognitive fatigue and depression are distinguishable. Consequently, we recommend assessing especially SADNESS scores to distinguish between MS related fatigue and depression.