A promising countermeasure for fatigue in sustained aviation operations is stimulant administration. However, well-controlled, aviation-relevant studies of the efficacy of medications such as Dexedrine are virtually nonexistent. In this investigation, flight performance, mood, and alertness were evaluated in 10 UH-60 pilots during sleep deprivation periods under Dexedrine or placebo. Relative to placebo, Dexedrine improved flight performance during straight-and-levels, climbs, descents, right turns, and a left-descending turn, with tendencies toward better performance during the left turns and the instrument landing system approach. Dexedrine markedly reduced subjective feelings of fatigue, confusion, and depression while increasing feelings of vigor. Central nervous system arousal was enhanced by Dexedrine relative to placebo. No significant side effects occurred, although Dexedrine was associated with mild asymptomatic increases in heart rate and BP. Thus, Dexedrine appears effective for the short-term sustainment of aviator performance during sustained operations. However, future work should investigate the efficacy of stimulants for longer-term use (e.g., more than 40 h of continuous wakefulness).