Declining aircrew performance during periods of sustained flight operations (SUSOPs) has underscored the need to develop effective countermeasures. This paper reports on the ability of the central nervous system (CNS) stimulant d-methamphetamine to alleviate the detrimental effects of a simulated SUSOPs on subjective fatigue. Subjective fatigue was repeatedly measured by three questionnaires. The simulated SUSOP started at 1800 and consisted of a 9-h planning session followed by 4 h of rest and a 14-h mission. After 6 h of sleep, the 9/4/14 work/rest/work pattern was repeated. At 4 1/2 h into the second mission, 13 subjects were administered 10 mg of d-methamphetamine/70 kg of body mass while 12 subjects received a placebo in a double-blind procedure. Administration of d-methamphetamine significantly reduced reported fatigue scores on the Addiction Research Center Inventory (ARCI), Mood Questionnaire (MQ), and sleepiness scores on the Stanford Sleepiness Scale (SSS).