Objectives: To analyze the factors associated with fatigue focusing on comorbidities in a large cohort of rheumatoid arthritis (RA). Methods: Cross-sectional analyses were performed on RA patients from the French COMEDRA cohort study, a nurse-led program for comorbidities management. Fatigue was assessed using Question 3 of the Rheumatoid Arthritis Impact of Disease (RAID) score on a 0-10 numerical rating scale (NRS). Fatigue was defined as acceptable if <= 2, moderate if 3 or 4, or severe if >= 5 out of 10. Using univariate and multivariate models, the relationship between fatigue and demographics, social, disease characteristics, comorbidities (cardiovascular, infections, cancer, pulmonary, osteoporosis, and psychiatric disorders), physical activity, quality of life, and treatments was investigated. Results: In total, 962 patients were analyzed. The mean fatigue score was 3.8 +/- 2.7, 40% of patients reported severe fatigue. Patients had an average of 1.8 additional morbid conditions, with anxiety/depression the most common (52%). In univariate analysis, severe fatigue was more frequent in women, in patients not working, and in those with less physical activity. It was associated with disease duration and activity, mHAQ, pain, sleeping and emotional difficulties. Severe fatigue correlated with Multimorbidity index assessing the number of morbid conditions and was associated with obesity, hypertension, COPD, and anxiety/depression. In multivariate models, the risk of severe fatigue was associated with female gender, disease activity, mHAQ, current treatment with NSAIDs and biologics, multimorbidity, obesity and anxiety/depression. Conclusions: Assessment of comorbidities, psychological health and physical activity should be taken into account in order to address frequent RA-related severe fatigue.