Objective. To investigate the relationship of fatigue severity to other clinical features in primary Sjögren's syndrome (SS) and to identify factors contributing to the physical and mental aspects of fatigue. Methods. We identified 94 subjects who met the American-European Consensus Group criteria for the classification of primary SS. Fatigue was assessed with a visual analog scale, the Fatigue Severity Scale (FSS), and the Profile of Fatigue (ProF). Associations with fatigue were compared using multivariate regression. Results. Abnormal fatigue, defined as an FSS score ≥4, was present in 67% of the subjects. Pain, helplessness, and depression were the strongest predictors of fatigue according to the FSS and the somatic fatigue domain of the ProF (ProF-S), both with and without adjustment for physiologic and serologic characteristics. Depression was associated with higher levels of fatigue; however, the majority of subjects with abnormal fatigue were not depressed. Anti-Ro/SSA-positive subjects were no more likely to report fatigue than seronegative subjects. The regression models explained 62% of the variance in FSS and 78% of the variance in ProF-S scores. Mental fatigue was correlated with depression and helplessness, but the model predicted only 54% of the variance in mental fatigue scores. Conclusion. Psychosocial variables are determinants of fatigue, but only partially account for it. Although fatigue is associated with depression, depression is not the primary cause of fatigue in primary SS. Investigation of the pathophysiologic correlates of physical and mental aspects of fatigue is needed to guide the development of more effective interventions.