Fatigue is the most commonly reported, most debilitating, and most poorly understood Post-Polio Sequelae (PPS). Postmortem studies of 50 years ago documented frequent and severe poliovirus-induced lesions within the Reticular Activating System (RAS). Recently, neuropsychological testing has documented marked attention deficits in polio survivors reporting severe fatigue. However, neither of these findings has yet been related to the pathophysiology of post-polio fatigue. Magnetic resonance imaging of the brain was performed in 22 polio survivors carefully screened to eliminate the effect of comorbidities. Subjects rated the severity of their daily fatigue and subjective problems with attention, cognition, and memory. Small discrete or multiple punctate areas of hyperintense signal (HS) in the reticular formation, putamen, medial leminiscus, or white matter tracts were imaged in 55% of the subjects reporting high fatigue and in none of those reporting low fatigue. The presence of HS significantly correlated with fatigue severity and subjective problems in attention, concentration, staying awake, recent memory, and thinking clearly. The lack of significant correlations between HS or fatigue severity and age, severity of the acute polio, depressive symptoms, or difficulty sleeping militates against these factors as either causing HS or producing fatigue. These preliminary findings suggest that poliovirus-induced lesions in the Brain Activating System may underlie the subjective fatigue and attention deficits reported by polio survivors.