The aims of this study were: (1) to obtain a systematic estimate of the levels of fatigue in representative samples of the major occupational groups of health care workers; (2) to examine the relationship between fatigue and mental health as a function of occupational and work role factors; and (3) to test the proposition that fatigue arises from a combination of poor mental health and high job stress. Questionnaire data from 7720 NHS Trust staff was used. Higher levels of fatigue were reported among health care workers in comparison with general population figures. Highest levels of general fatigue, the subjective sensation of tiredness, were experienced by doctors (especially women doctors), professions allied to medicine and managers. Highest levels of fatigability, the onset of symptoms after exertion, were experienced by ancillary and nursing staff. Both general fatigue and fatigability were associated with high levels of psychological distress. Support was also found for the proposition that fatigue arises from a combination of poor mental health and high work demands.