The aim of this cross-sectional descriptive study was to determine whether people with multiple sclerosis differentially experience physical and mental fatigue, and whether the pattern of fatigue is influenced by mood, disease duration, or disease course. Seventy-eight consecutive out-patients with multiple sclerosis were asked to complete the Fatigue Rating Scale (FRS) and the Hospital Anxiety and Depression Scale (HAD). Sixty-eight (87%) subjects completed the questionnaires. Fifty-eight (85%) subjects in this group scored above the recommended cut-off for fatigue on the FRS scale. Both the mental fatigue score and the total fatigue score were positively correlated with the depression and anxiety scores on the HAD scale. There was no significant correlation between the physical fatigue score and either of the HAD subscale scores. There was no significant association between duration of disease or disease course and the total scores or subscale scores of the FRS and HAD. This is the first reported study to differentiate between mental and physical fatigue in multiple sclerosis and to demonstrate a significant correlation between fatigue and mood level. This has important implications for the effective treatment of fatigue in multiple sclerosis.