Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating, long-term condition characterised by extreme fatigue (worsened by exertion), muscle and joint pain, and sleep disturbance. Post-exertional fatigue has been demonstrated previously following physical exercise, but not from mental exertion alone. Purpose: The aim of this exploratory study was to assess the 'delayed fatigue effect,'in this instance fatigue two days post-challenge, following a cognitively fatiguing task. Methods: Thirty-two participants (23 women; mean age 44, SD = 11.24; mean illness duration nine years, SD = 7.32) completed the Cambridge Neuropsychological Test Automated Battery, which acted as the cognitive challenge. Self-report measures were also completed that assessed fatigue (Multidimensional Fatigue Inventory; MFI), and anxiety and depression (Hospital Anxiety and Depression Scale; HADS) pre-and two days post-testing. Results: Significant differences were found between pre-and posttest measures in three MFI sub-scales of fatigue (general, mental, and physical) and on the depression scale of the HADS. However, there were no significant changes in motivation, activity level, or self-reported anxiety scores. Conclusions: These findings are suggestive of post-exertional symptom exacerbation following mental effort. This may have implications for working environments that present cognitive demands to individuals with ME/CFS.