Background: Modifiable lifestyle factors and comorbidity in MS have been associatedwith an increased prevalence of fatigue in MS. However, most studies do not distinguishbetween cognitive and motor fatigue.Objectives: To investigate whether the severity of motor and cognitive fatigue differs inrelation with smoking, comorbidity, anxiety and depression in MS.Methods: Participants completed questionnaires assessing smoker type (non-smoker,stopped smoker, current smoker) and comorbidity score (0-7) taking in account diabetes,hypertension, hypercholesterolemia, cardiovascular, gastrointestinal, renal and locomotordisorders. Fatigue severity, anxiety and depression were assessed at baseline and month 12 using the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Hospital Anxiety and Depression Scale (HADS). Significant relations between variables were determined with Spearman correlations and averages were compared with a t-test.Results: Baseline data revealed the presence of at least moderate motor and cognitivefatigue in respectively 78% and 59% of the 119 participants. Motor fatigue correlated withEDSS (r=0.39, p< 0.001) whereas cognitive fatigue did not. About one quarter of participants, 31/119 (26.05%) were current smokers, three quarters of participants presented with at least one comorbidity (88/119), more than half of them (49/88) reported at least 2 comorbidities. Smoking status and having a higher comorbidity score was significantly associated with higher motor fatigue scores (respectively rho =0.22; p=0.01 and rho = 0.24; p< 0.01), but not with cognitive fatigue scores. Participants being anxious and/or depressed as based on the subscales of the HADS scores reported significantly more severe fatigue, both cognitive (+7.4; p< 0.01and +7.5; p< 0.05) and motor (+4.2; p< 0.01 and +4.2; p< 0.05). Cognitive FSMC scores slightly decreased at month 12 (-1.2; p< 0.05). Changes in motor and cognitive FSMC scores correlated significantly with changes in HADS scores.Conclusion: Our findings are indicating distinct associations for cognitive and motorfatigue severity in MS. While comorbidities and smoking appeared to be related to motorfatigue, anxiety and depression affected both.