BackgroundCognitive behavioral therapy (CBT) is an evidence-based intervention for severe fatigue. Changes in patients’ fatigue scores following CBT might reflect not only the intended relief in fatigue but also response shift, a change in the meaning of patients’ self-evaluation. Objectives were to (1) identify the occurrence of response shift in patients undergoing CBT, (2) determine the impact of response shift on the intervention effect, and (3) investigate whether changes in fatigue-related cognitions and perceptions, targeted during CBT, are associated with response shift.MethodsData of three randomized controlled trials testing the efficacy of CBT in individuals with chronic fatigue syndrome (CFS,n= 222), cancer (n= 123), and diabetes (n= 107) were re-analyzed. Fatigue severity was measured with 8 items from the Checklist Individual Strength, a valid and widely used self-report questionnaire. Structural equation modelling was applied to assess lack of longitudinal measurement invariance, as indication of response shift.ResultsAs expected, in all three trials, response shift was indicated in the CBT groups, not the control groups. Response shift through reprioritization was indicated for the items “Physically, I feel exhausted” (CFS) and “I tire easily” (cancer, diabetes), which becamelessvs.moreimportant to the measurement of fatigue, respectively. However, this did not affect the intervention effects. Some changes in cognitions and perceptions were associated with the response shifts.ConclusionsCBT seems to induce response shift through reprioritization across patient groups, but its occurrence does not affect the intervention effect. Future research should corroborate these findings and investigate whether patients indeed change their understanding of fatigue.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12529-022-10111-8.