Fatigue is the most commonly reported and most disabling of all post-polio sequelae (PPS). Bromocriptine mesylate (Parlodel) was employed in a placebo-controlled trial in five survivors of paralytic polio who continued to report moderate to severe daily fatigue after complying with the conservative treatments prescribed for PPS. Placebo was given for 4 wk followed by increasing doses of bromocriptine mesylate, administered at 12:00 pm for 28 days, which reached a total dose of 12.5 mg/day. Three subjects reported marked symptom improvement on bromocriptine but not on placebo. Their reported difficulty with attention, concentration, word finding, mind wandering, memory, thinking clearly, and fatigue on awakening was significantly negatively correlated with days on bromocriptine but not with days on placebo. Before the drug trial began, responders had clinically impaired performance on neuropsychologic tests of attention and information processing speed, more than twice as many hyperintensities on magnetic resonance imaging of the brain, abnormally low fasting adrenocorticotropic hormone levels, and nearly double the mean plasma prolactin level compared with nonresponders. The implications of these findings for the pathophysiology of fatigue are discussed. A double-blind, placebo-controlled, multicenter study will be needed to confirm bromocriptine's efficacy in treating attentionally and neurophysiologically impaired polio survivors whose severe and disabling fatigue does not respond to conservative therapies.