Sleep deprivation and alcohol both impair driving performance. This study assessed the interactive effect of low-dose alcohol and extended wakefulness. The combination of extended wakefulness and low-dose alcohol had significant deleterious effects on reaction time and lapses (PVT) and variation in lane position and speed (AusEd). Extended wakefulness (18–21 hours awake) combined with low-dose alcohol (0.03% BAC) resulted in more lapses (t = −2.75, P < 0.05) and greater variation in lane position (t = −3.94, P < 0.01) and speed (t = −2.79, P < 0.05) than did a BAC of 0.05% in a rested state. The combination of legal low-dose alcohol and extended wakefulness results in impairment worse than that at an alcohol level known to increase accident risk. Avoiding alcohol when driving after extended wakefulness may reduce accident risk.