INTRODUCTION The efficacy of Dexedrine for sustaining aviator performance despite 64 h of extended wakefulness was investigated. This study was conducted to extend the findings of earlier research that had proven the efficacy of Dexedrine during shorter periods (i.e., 40 h) of sleep deprivation. METHODS Dexedrine (10 mg) or placebo was given at midnight, 0400, and 0800 hours on two deprivation days in each of two 64-h cycles of continuous wakefulness. Test sessions consisting of simulator flights, electroencephalographic evaluations, mood questionnaires, and cognitive tasks were conducted at 0100, 0500, 0900, 1300, and 1700 hours on both deprivation days. Two nights of recovery sleep separated the first and second 64-h sleep-deprivation cycles. RESULTS Simulator flight performance was maintained by Dexedrine throughout sleep deprivation. The most benefit occurred at 0500 and 0900 hours (around the circadian trough) on the first deprivation day, but continued throughout 1700 hours (after 58 h awake) on the second day. Dexedrine suppressed slow-wave EEG activity which occurred under placebo after 23 h awake and continued to exert this effect throughout 55 h (and sometimes 59 h) of deprivation. The drug sustained self-perceptions of vigor while reducing fatigue and confusion. Recovery sleep was slightly less restful under Dexedrine. CONCLUSIONS Dexedrine sustained aviator performance and alertness during periods of extended wakefulness, but its use should be well controlled. Although effective, Dexedrine is no replacement for adequate crew rest management or restful sleep.