Summary Cognitive performance is impaired by fatigue arising from sustained wakefulness and alcohol. Three recent papers directly compared the effects of increasing fatigue and blood alcohol concentration (%BAC) to provide a framework for understanding fatigue-related cognitive impairment. While the expression of fatigue-related cognitive impairments in terms of %BAC equivalents is sound, the methodology in each study was flawed in that the statistics used to compare the effects of %BAC and fatigue on cognition did not account for variation between or within each condition. The point estimates of the difference between a baseline and any level of fatigue or %BAC provided no indication of the size of difference that could reasonably be expected by chance. Importantly, all studies showed that variation increased as cognitive performance declined because of both increasing fatigue and %BAC. The current study compared the effect of increasing levels of %BAC and fatigue on the simple reaction task from the CogState test battery on 40 healthy adults using statistical methods that account for intra-individual and within-group variability in performance. After 24 h of sustained wakefulness and with 0.08%BAC, individuals showed maximal cognitive impairment; however, the magnitude of impairment found for fatigue was equivalent only to that observed for 0.05%BAC. Re-analysis of the data using percentage change scores indicated that the magnitude of fatigue-related cognitive impairment was much greater than that detected for 0.08%BAC. This suggests that previous studies that have not accounted for variability in the performance data have overestimated the effect of fatigue on cognitive performance.