We sought to identify clinical characteristics and socio-demographic variables associated with longitudinal patterns of fatigue in multiple sclerosis (MS) patients. A questionnaire including the Fatigue Severity Scale (FSS) was mailed to a community sample of 502 MS patients three times 1 year apart. Three patterns of fatigue were defined: persistent fatigue (PF) (mean FSS score > or = 5 at all time-points), sporadic fatigue (SF) (mean FSS score > or = 5 at one or two time-points) and no fatigue (mean FSS score < 5 at all time-points). Among the 267 (53%) patients who responded at all time-points, 101 [38%, 95% confidence intervals (CI) 32-44] had persistent, 98 (37%, 95% CI 31-43) sporadic and 68 (25%, 95% CI 20-31) no fatigue. Persistent and sporadic fatigue were more common in patients with, increased neurological impairment (P < 0.001), primary progressive MS (P = 0.01), insomnia (P < 0.001), heat sensitivity (P < 0.001), sudden-onset fatigue (P < 0.001) or mood disturbance (P < 0.001) compared with patients without fatigue. Multivariable analysis showed that depression (PF P = 0.02, SF P < 0.001), heat sensitivity (PF P = 0.04, SF P = 0.02) and physical impairment (PF P = 0.004, SF P = 0.01) were associated with both sporadic and persistent fatigue. About 75% of the patients had persistent or sporadic fatigue over a 2 years observation period. Multivariable analyses confirmed a significant association between levels of depression, physical impairment and persistent fatigue.