Objective: Severe fatigue is highly prevalent in various chronic diseases. Disease-specific fatigue models have been developed, but it is possible that fatigue-related factors in these models are similar across diseases. The purpose of the current study was to determine the amount of variance in fatigue severity explained by: (a) the specific disease, (b) factors associated with fatigue across different chronic diseases (transdiagnostic factors), and (c) the interactions between these factors and specific diseases. Method: Data from 15 studies that included 1696 patients with common chronic diseases and disorders that cause long-term disabilities were analyzed. Linear regression analysis with the generalized least-squares technique was used to determine fatigue-related factors associated with fatigue severity, that is, demographic variables, health-related symptoms and psychosocial variables. Results: Type of chronic disease explained 11% of the variance noted in fatigue severity. The explained variance increased to 55% when the transdiagnostic factors were added to the model. These factors were female sex, age, motivational and concentration problems, pain, sleep disturbances, physical functioning, reduced activity and lower self-efficacy concerning fatigue. The predicted variance increased to 61% when interaction terms were added. Analysis of the interactions revealed that the relationship between fatigue severity and relevant predictors mainly differed in strength, not in direction. Conclusions: Fatigue severity can largely be explained by transdiagnostic factors; the associations vary between chronic diseases in strength and significance. This suggests that severely fatigued patients with different chronic diseases can probably benefit from a transdiagnostic fatigue-approach which focuses on individual patient needs rather than a specific disease.