Fatigue in military aviation is a significant safety and operational problem resulting in diminished alertness and performance. Research demonstrates that stimulant medications maintain alertness and performance in sleep-deprived aircrew. However, these studies control many of the variables present during combat operations. Few studies have evaluated fatigue or the factors and effects associated with stimulant use in fighter aircrew during combat operations. The study consisted of three questionnaires administered to 29 deployed F-1 5E aircrew participants. An initial questionnaire compiled demographic and sleep behavior data. Pre- and postflight questionnaires for each sortie collected substance use, fatigue, and physical symptoms data. Regression analysis identified variables associated with in-flight stimulant use. Surveys were completed for 111 sorties averaging 7.6 h in duration. Stimulants were used on 35% of sorties an average of 2.8 h after takeoff. Stimulant use was associated with a decrease in in-flight and postflight fatigue without significant differences in postflight symptoms. Sorties airborne during the circadian trough, longer sortie durations, and preflight hypnotic use displayed statistically significant associations with in-flight stimulant use. In-flight stimulants decrease fatigue during combat operations without significant postflight symptoms. During combat, stimulants were used earlier, at lower doses, and on shorter sorties than previously thought. The factors associated with stimulant use are potentially modifiable by improving training and aircrew scheduling practices. Furthermore, current policies authorizing stimulant use, based primarily on sortie duration, should also consider hypnotic use, inconsistent aircrew scheduling, and circadian disruption.