Clinical reports suggest that many survivors of childhood cancer experience fatigue as a long-term effect of their treatment. To investigate this issue further, we assessed the level of fatigue in young adult survivors of childhood cancer. We compared the results with a group of young adults with no history of cancer. The impact of demographic, medical and treatment factors and depressive symptoms on survivors' fatigue was studied. Participants were 416 long-term survivors of childhood cancer (age range 16-49 years, 48% of whom were female) who had completed treatment an average of 15 years previously and 1026 persons (age range 16-53 years, 55% female) with no history of cancer. All participants completed the Multidimensional Fatigue Inventory (MFI-20), a self-report instrument consisting of five scales (general fatigue, physical fatigue, mental fatigue, reduced activity, reduced motivation) and the Center for Epidemiologic Studies Depression Scale (CES-D). Small differences were found in the mean scores for the different dimensions of fatigue between the long-term survivors and controls (range effect sizes -0.34 to 0.34). Women experienced more fatigue than men. Logistic regression revealed that being female and unemployed were the only demographic characteristics explaining the various dimensions of fatigue. With regard to medical and treatment factors, diagnosis and severe late effects/health problems were associated with fatigue. Finally, depression was significantly associated with fatigue on all subscales. Our clinical practice suggests a difference in fatigue in young adult childhood cancer survivors and their peers. This could not be confirmed in this study using the MFI-20. The well known correlation between fatigue and depression was confirmed in our study. Further research is needed to clarify the undoubtedly complex somatic and psychological mechanisms responsible for the development, maintenance and treatment of fatigue in childhood cancer survivors.