This study investigated health-related quality of life (HRQoL; physical functioning and psychological distress) in an Australian chronic fatigue syndrome (CFS) population. The aims of the study were to compare HRQoL in those with CFS to the normal population, and to investigate the extent to which sociodemographic (age, gender, partner status, education), illness-related (illness duration, symptom frequency), and fatigue severity (physical, mental) variables predicted HRQoL. A total of 139 people meeting CFS criteria completed questionnaires. HRQoL was assessed using standardised measures of distress and physical functioning. Compared with norms, those with CFS obtained significantly lower scores on all physical functioning areas, whereas 63% of participants reported clinically significant psychological distress. Hierarchical regression analyses indicated that physical fatigue severity and symptom frequency were the strongest predictors of deficits in physical domain HRQoL. Physical HRQoL outcomes were also predicted by mental fatigue severity, older age, and female gender. All predictors were unrelated to psychological distress apart from weak positive associations with physical fatigue and symptom frequency. Results identify a potent set of predictors of HRQoL and show that CFS has a pervasive negative impact on quality of life, particularly physical and psychological functioning.