Fatigue is a serious issue for the rail industry, increasing inefficiency and accident risk. The performance of 20 train drivers in a rail simulator was investigated at low, moderate and high fatigue levels. Psychomotor vigilance (PVT), self-rated performance and subjective alertness were also assessed. Alertness, PVT reaction times, extreme speed violations (>25% above the limit) and penalty brake applications increased with increasing fatigue level. In contrast, fuel use, draft (stretch) forces and braking errors were highest at moderate fatigue levels. Thus, at high fatigue levels, errors involving a failure to act (errors of omission) increased, whereas incorrect responses (errors of commission) decreased. The differential effect of fatigue on error types can be explained through a cognitive disengagement with the virtual train at high fatigue levels. Interaction with the train reduced dramatically, and accident risk increased. Awareness of fatigue-related performance changes was moderate at best. These findings are of operational concern.